MedWorm: Hereditary Nonpolyposis Colorectal Cancer

Lymphoepithelioma-like carcinoma of the colon.

International Journal of Clinical and Experimental Pathology — Tue, 07 Feb 2012 13:36:02 +0100

Authors: Delaney D, Chetty R Abstract An 85-year old female had a polypoid tumour in the sigmoid colon that histologically conformed to a lymphoepithelioma-like (LEL) carcinoma. The tumour was arranged in cords, chains, clusters and microalveoli of pleomorphic, irregular cells set within a dense intratumoral lymphocytic stroma. The tumour was EBV-negative and showed loss of MLH-1 and PMS-2 mismatch repair proteins. The patient did not fulfil the criteria for HNPCC. Only 5 other cases of primary colonic LEL carcinoma have been described previously and only one case appears to have an unequivocal association with EBV. In addition, one of the cases was encountered in a HNPCC patient. This is an unusual morphologic variant of a microsatellite unstable tumour with a LEL pattern, not ass...

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Germline promoter hypermethylation of tumor suppressor genes in gastric cancer.

World Journal of Gastroenterology : WJG — Sat, 07 Jan 2012 05:00:00 +0100

CONCLUSION: Mosaic germline epimutation of the MLH1 gene is present in suspected hereditary GC patients in China but at a very low level. Germline epimutation of the CDH1 or P16(INK4a) gene is not a frequent event. PMID: 22228973 [PubMed - in process] (Source: World Journal of Gastroenterology : WJG)

The founder Ashkenazi Jewish mutations in the MSH2 and MSH6 genes in Israeli patients with gastric and pancreatic cancer

Familial Cancer — Wed, 04 Jan 2012 17:03:09 +0100

Abstract The genetic basis for gastric and pancreatic cancer is largely undetermined. These cancers are overrepresented in hereditary non polyposis colon cancer (HNPCC), inherited cancer syndrome attributed to germline mutations primarily in the MSH2, MLH1 and MSH6 genes. Among Ashkenazi Jewish HNPCC cases, recurring mutations in the MSH2 (1906G>C; A636P) and MSH6 (c.3984_3987dupGTCA; c.3959_3962delCAAG) genes can be detected. The MSH6*c.3984_3987dupGTCA mutation was recently detected in an Ashkenazi family with inherited gastric cancer. We hypothesized that it may be possible to detect the recurring MSH2 and MSH6 mutations in Jewish individuals with familial and sporadic gastric and pancreatic cancer. To test this notion, we genotyped 143 unrelated Jewish Israeli patients...

Hereditary nonpolyposis colorectal cancer (Lynch syndrome I) in a 15-year-old male

International Journal of Colorectal Disease — Tue, 27 Dec 2011 06:34:21 +0100

Content Type Journal ArticleCategory Letter to the EditorPages 1-2DOI 10.1007/s00384-011-1391-5Authors F. de la Portilla, Coloproctology Unit, Gastrointestinal Surgery Department, Virgen del Rocio University Hospital, Avda. Manuel Siurot s/n, 41013 Seville, SpainI. Ramallo, Coloproctology Unit, Gastrointestinal Surgery Department, Virgen del Rocio University Hospital, Avda. Manuel Siurot s/n, 41013 Seville, SpainS. Pardo, Coloproctology Unit, Gastrointestinal Surgery Department, Virgen del Rocio University Hospital, Avda. Manuel Siurot s/n, 41013 Seville, SpainE. León, Urology Unit, University Hospital Virgen del Rocio, Seville, SpainJ. M. Díaz-Pavón, Coloproctology Unit, Gastrointestinal Surgery Department, Virgen del Rocio University Hospital, Avda. Manuel Siurot s/n, 41013 Sevill...

T[20] repeat in the 3′-untranslated region of the MT1X gene: a marker with high sensitivity and specificity to detect microsatellite instability in colorectal cancer

International Journal of Colorectal Disease — Tue, 22 Nov 2011 17:57:43 +0100

Conclusions Our results suggest that MT1XT20 represents a sensitive and specific marker for MSI testing and could be included in a complete set of MSI markers for the confident identification of familial or sporadic dMMR patients in CRCs. Content Type Journal ArticleCategory Original ArticlePages 1-10DOI 10.1007/s00384-011-1365-7Authors Luca Morandi, Department of Haematology and Oncological Sciences L. and A. Seragnoli, Section of Anatomic Pathology at Bellaria Hospital, University of Bologna, via Altura 3, 40139 Bologna, ItalyDario de Biase, Department of Experimental Pathology, University of Bologna, via San Giacomo 14, 40126 Bologna, ItalyMichela Visani, Department of Experimental Pathology, University of Bologna, via San Giacomo 14, 40126 Bologna, ItalyAdriana M...

Mutation and association analyses of the candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A in patients with unexplained MSH2-deficient tumors

Familial Cancer — Tue, 15 Nov 2011 16:48:45 +0100

Abstract Lynch syndrome (Hereditary non-polyposis colorectal cancer/HNPCC) is a cancer susceptibility syndrome which is caused by germline mutations in DNA mismatch repair (MMR) genes, in particular MLH1 and MSH2. A pathogenic germline mutation in the respective MMR gene is suggested by the finding of a loss of a mismatch repair protein in tumor tissue on immunohistochemical staining combined with an early age of onset and/or the familial occurrence of colorectal cancer. Pathogenic germline mutations are identifiable in around 60% of patients suspected of Lynch syndrome, depending on the familial occurrence. The aim of the present study was to identify novel susceptibility genes for Lynch syndrome. 64 Healthy controls and 64 Lynch syndrome patients with no pathogenic MSH2 m...

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Familial adenomatous polyposis, suspected HNPCC, and Crohn's disease: Two cases

Inflammatory Bowel Diseases — Sun, 13 Nov 2011 05:00:00 +0100

(Source: Inflammatory Bowel Diseases)

Regulation of hMSH2-hMSH6 ATPase [Molecular Bases of Disease]

Journal of Biological Chemistry — Fri, 11 Nov 2011 05:00:00 +0100

The mechanics of hMSH2-hMSH6 ATP binding and hydrolysis are critical to several proposed mechanisms for mismatch repair (MMR), which in turn rely on the detailed coordination of ATP processing between the individual hMSH2 and hMSH6 subunits. Here we show that hMSH2-hMSH6 is strictly controlled by hMSH2 and magnesium in a complex with ADP (hMSH2(magnesium-ADP)-hMSH6). Destabilization of magnesium results in ADP release from hMSH2 that allows high affinity ATP binding by hMSH6, which then enhances ATP binding by hMSH2. Both subunits must be ATP-bound to efficiently form a stable hMSH2-hMSH6 hydrolysis-independent sliding clamp required for MMR. In the presence of magnesium, the ATP-bound sliding clamps remain on the DNA for ∼8 min. These results suggest a precise stepwise kinetic mechanism...

Surgery for colonic cancer in HNPCC: total vs segmental colectomy

Colorectal Disease — Thu, 10 Nov 2011 10:36:22 +0100

Conclusion Patients with HNPCC have a significant risk of MCC after SC. This is eliminated by performing TC as the primary operation for colonic cancer. (Source: Colorectal Disease)

Aspirin 'blocks genetic bowel cancer'

NHS News Feed — Fri, 28 Oct 2011 17:45:00 +0100

Conclusion This was a well-designed long-term trial. It examined the effect of regular aspirin consumption on bowel cancer rates in a specific group of patients with a raised risk of developing bowel and other cancers. The results indicate that regular treatment with aspirin is an effective method of preventing bowel cancer in this group of high-risk patients. The study had several strengths, particularly related to design of the trial. For example, even at the end of the study neither the participants nor investigators were made aware of which individuals had received aspirin and which had received placebo. This helps ensure an unbiased analysis of long-term follow-up data, increasing the confidence we can have in the results. There are, however, several things to consider when interpreti...

G-C heterozygosis in mutS homolog2 as a risk factor to hereditary nonpolyposis colon cancer in the absence of a family medical history

Indian Journal of Human Genetics — Mon, 17 Oct 2011 04:00:00 +0100

Jorge Alfonso Arvayo-Zatarain, José Manuel Grijalva-Chon, Reina Castro-Longoria, Alejandro Varela-RomeroIndian Journal of Human Genetics 2011 17(2):90-93To detect the presence of point mutations in a small section of the mutS homolog2 (MSH2) gene in both healthy and affected persons treated at the General Hospital of the State of Sonora, a 353 base pair section of the MSH2 gene was amplified and sequenced from six persons affected by hereditary nonpolyposis colorectal cancer and from 19 healthy persons. The affected persons did not show the mutations reported in the scientific literature; however, six healthy persons were heterozygote and mutant-allele carriers. The heterozygote condition implies that carriers are candidates for the development of colorectal cancer. However, it is i...

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A meta‐analysis of the prevalence of somatic mutations in the hMLH1 and hMSH2 genes in colorectal cancer

Colorectal Disease — Sat, 01 Oct 2011 04:00:00 +0100

Conclusion: Somatic mutations in the hMLH1 and hMSH2 genes play a vital role in CRC and a high prevalence was found in this meta‐analysis. Furthermore, more studies are needed which focus on somatic mutations in the American population and in patients with MSI‐L and MSS. (Source: Colorectal Disease)

[Bladder cancer at an early age in father and son.]

Der Urologe. Ausg. A — Fri, 23 Sep 2011 04:00:00 +0100

We report on a father and son who developed this tumour at the ages of 45 and 35. Testing various genetic markers including the mismatch repair proteins MLH1, MSH2 and MSH6, whose loss is associated with a higher risk for hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome), did not point to a familial disease. Thus the heavy smoking habits of the two patients must be considered as causal. PMID: 21938565 [PubMed - as supplied by publisher] (Source: Der Urologe. Ausg. A)

Acute myeloid leukaemia associated with Muir‐Torre variant of hereditary non‐polyposis colon cancer (HNPCC): implications for inherited and acquired mutations in DNA mismatch repair genes

British Journal of Haematology — Tue, 13 Sep 2011 04:00:00 +0100

(Source: British Journal of Haematology)

Two novel mutations in hMLH1 gene in Iranian hereditary non-polyposis colorectal cancer patients

Familial Cancer — Thu, 08 Sep 2011 05:56:52 +0100

In this study, we screened hMLH1 gene in a group of Iranian HNPCC patients using polymerase chain reaction-single strand conformational polymorphism and direct sequencing methods. Here we report two novel frameshift mutations in this gene in our studied population. One of them results from a deletion of “T” at codon 36, exon 1 which causes premature stop codon and a truncated protein. The other results from a deletion of “T” at codon 753, exon 19 causing a delayed stop codon. There are a variety of the reported novel mutations in hMLH1 gene studies. Identification of these mutations is necessary in different populations and can help the management of colorectal cancer in these populations by screening, by prevention strategies, and by following up the suspected HNPCC familie...

Microsatellite instability in sporadic gastric cancer : Its prognostic role and guidance for 5‐FU based chemotherapy after R0 resection

International Journal of Cancer — Thu, 25 Aug 2011 23:00:00 +0100

AbstractMicrosatellite instability (MSI) is characterized by novel sized alleles detected in microsatellite sequences found in the DNA of carcinoma tissue that is not present in normal constitutional DNA. Although MSI has been reported along with several types of cancers, it is thought to be an important mechanism of hereditary nonpolyposis colorectal cancer (HNPCC), which occurs by germline mutations in one of the DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. The clinicopathological characteristics of MSI+ colorectal cancers have been widely studied: proximal location, reduced lymph node metastasis and better overall survival rate.1 Recently, several studies analyzed the relationship between MSI and benefits from adjuvant 5‐Fluorouracil (5‐FU)‐based chemotherap...

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Familial pancreatic cancer and hereditary syndromes: screening strategy for high-risk individuals

Journal of Gastroenterology — Wed, 17 Aug 2011 05:55:29 +0100

Abstract Globally, and almost evenly across nations, a familial disposition can be found in 4–10% of patients with pancreatic cancer (PC). A family history of PC is a risk for this disease and the risk level changes in correlation with the number of affected relatives. Several hereditary syndromes with potential germline mutation also have a high risk for PC; however, little is yet known regarding the genes responsible for familial pancreatic cancer (FPC). Characteristics of FPC cases are similar to those of other familial tumors, including younger onset than in sporadic cases and an ethnic difference (Ashkenazi Jewish > other Caucasian). Other risks resemble those of sporadic cases and include smoking and diabetes mellitus. People with several genetic syndr...

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Laboratory Investigation AOP — Sun, 07 Aug 2011 23:00:00 +0100

Authors: Lucia Gullotti, Jacqueline Czerwitzki, Jutta Kirfel, Peter Propping, Nils Rahner, Verena Steinke, Philip Kahl, Christoph Engel, Roland Schüle, Reinhard Buettner & Nicolaus Friedrichs (Source: Laboratory Investigation AOP)

Mismatch repair genes expression defects & association with clinicopathological characteristics in colorectal carcinoma.

Indian J Med Res — Mon, 01 Aug 2011 04:00:00 +0100

This study was aimed to determine the frequency of abnormal MMR gene protein expression in colorectal carcinoma in Northern Peninsular Malaysia using immunohistochemistry. Methods: Clinicopathological information was obtained from 148 patients' records who underwent bowel resection for colorectal cancer (CRC) at the three hospitals in Malaysia. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 proteins were performed on paraffin embedded tissue containing carcinoma. Results: A total of 148 subjects and 150 colorectal carcinomas of sporadic and hereditary types were assessed. Three patients had synchronous tumours. Twenty eight cancers (18.6%) from 26 subjects (17.6%) had absent immunohistochemical expression of any one of the MMR gene proteins. This comprised absent MLH1 only - 3 cancers,...

Deficiency in DNA mismatch repair increases the rate of telomere shortening in normal human cells

Human Mutation — Wed, 27 Jul 2011 12:11:15 +0100

In this study we show that there is a high level of instability within telomeric DNA with a tendency toward deletions in tumor‐derived MMR defective cell lines. We downregulated MSH2 expression in a normal fibroblast cell line and isolated four clones, with differing levels of MSH2 depletion. The telomere‐shortening rate was measured at the Xp/Yp, 12q, and 17p telomeres in the MSH2 depleted and three control clones. Interestingly the mean telomere‐shortening rate in the clones with MSH2 depletion was significantly greater than in the control clones. This is the first demonstration that MSH2 deficiency alone can lead to accelerated telomere shortening in normal human cells. Hum Mutat 32:939–946, 2011. © 2011 Wiley‐Liss, Inc. (Source: Human Mutation)

Purification, crystallization and preliminary X-ray diffraction analysis of the human mismatch repair protein MutSβ

Acta Crystallographica Section F — Mon, 25 Jul 2011 23:00:00 +0100

MutSβ is a eukaryotic mismatch repair protein that preferentially targets extrahelical unpaired nucleotides and shares partial functional redundancy with MutSα (MSH2–MSH6). Although mismatch recognition by MutSα has been shown to involve a conserved Phe-X-Glu motif, little is known about the lesion-binding mechanism of MutSβ. Combined MSH3/MSH6 deficiency triggers a strong predisposition to cancer in mice and defects in msh2 and msh6 account for roughly half of hereditary nonpolyposis colorectal cancer mutations. These three MutS homologs are also believed to play a role in trinucleotide repeat instability, which is a hallmark of many neurodegenerative disorders. The baculovirus overexpression and purification of recombinant human MutSβ and three truncation mutants are presented her...

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Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome

Journal of Medical Genetics — Wed, 20 Jul 2011 23:00:00 +0100

Background A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10–15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected. Methods Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours. Results and conclusion A deletion in the LRRFIP2 (leucine-rich repeat flightless-interacting protein 2) gene flanking the MLH1 gene was detected, which turned out to be a paracentric inversion on chromosome 3p22.2 creating two new stable fu...

Factors affecting encouragement of relatives among families with Lynch syndrome to seek medical assessment

Familial Cancer — Tue, 21 Jun 2011 20:56:58 +0100

Abstract Lynch syndrome (HNPCC) is an autosomal dominant hereditary cancer syndrome, and members of affected families are at-risk for developing colorectal and other associated tumors. Such individuals should disseminate familial genetic information, so they can seek specific medical assessment or genetic testing to reduce mortality and morbidity rates by early detection. Since published results have been encouraging, we explored which factors influence the likelihood of good communication within families regarding medical assessment. We studied 40 individuals from 33 families who satisfied the Japanese clinical criteria for Lynch syndrome and their relatives at our hospital. We determined the status of relatives of the 40 individuals after genetic counseling and testing u...

Limited impact on self-concept in individuals with Lynch syndrome; results from a national cohort study

Familial Cancer — Tue, 21 Jun 2011 18:34:17 +0100

This study provides the first extended use of the Lynch syndrome self-concept scale and suggests that the majority of the Danish mutation carriers adapt well to the situation, though knowledge about the increased risk of cancer seem to have a greater impact in females, individuals with less education and those with experience of cancer in close relatives. Content Type Journal ArticlePages 1-7DOI 10.1007/s10689-011-9459-5Authors Helle Vendel Petersen, Clinical Research Centre, Hvidovre University Hospital, Copenhagen University, Copenhagen, DenmarkMary Jane Esplen, Division of Behavioral Science and Health, Toronto General Research Institute, University Health Network, Toronto, CanadaSteen Ladelund, Clinical Research Centre, Hvidovre University Hospital, Copenhagen University, Cope...

Familial colorectal cancer: eleven years of data from a registry program in Switzerland

Familial Cancer — Tue, 14 Jun 2011 05:59:43 +0100

Abstract Deleterious germ-line variants involving the DNA mismatch repair (MMR) genes have been identified as the cause of the hereditary nonpolyposis colorectal cancer syndrome known as the Lynch syndrome, but in numerous familial clusters of colon cancer, the cause remains obscure. We analyzed data for 235 German-speaking Swiss families with nonpolyposis forms of colorectal cancer (one of the largest and most ethnically homogeneous cohorts of its kind) to identify the phenotypic features of forms that cannot be explained by MMR deficiency. Based on the results of microsatellite instability analysis and immunostaining of proband tumor samples, the kindreds were classified as MMR-proficient (n = 134, 57%) or MMR-deficient (n = 101, 43%). In 81 of the lat...

An American founder mutation in MLH1

International Journal of Cancer — Sun, 12 Jun 2011 23:00:00 +0100

AbstractMutations in the mismatch repair genes cause Lynch syndrome (LS), conferring high risk of colorectal, endometrial and some other cancers. After the same splice site mutation in the MLH1 gene (c.589‐2A>G) had been observed in 4 ostensibly unrelated American families with typical LS cancers, its occurrence in comprehensive series of LS cases (Mayo Clinic, Germany and Italy) was determined. It occurred in 10 out of 995 LS mutation carriers (1.0%) diagnosed in the Mayo Clinic diagnostic laboratory. It did not occur among 1803 cases tested for MLH1 mutations by the German HNPCC consortium, while it occurred in 3 probands and an additional 5 family members diagnosed in Italy. In the U.S., the splice site mutation occurs on a large (∼4.8 Mb) shared haplotype that also harbors the v...

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Pulmonary sclerosing hemangioma in a 21-year-old male with metastatic hereditary non-polyposis colorectal cancer: Report of a case

World Journal of Surgical Oncology — Sun, 05 Jun 2011 23:00:00 +0100

Conclusions: Cases have been published with familial adenomatous polyposis (FAP) and simultaneous SH. FAP, Gardner syndrome and Li-Fraumeni syndrome, however, had been ruled out in the present case. To the best of our knowledge, this is the first report describing SH associated with Lynch syndrome. (Source: World Journal of Surgical Oncology)

BMPR1A Mutations in Hereditary Nonpolyposis Colorectal Cancer Without Mismatch Repair Deficiency

Gastroenterology — Wed, 01 Jun 2011 23:00:00 +0100

Families with the clinical picture of hereditary nonpolyposis colorectal carcinoma fall into 2 categories—Lynch syndrome associated with hereditary defects in DNA mismatch repair (MMR) and familial colorectal cancer type X (FCCX) with no detectable mutation in DNA MMR genes. The predisposing gene(s) for FCCX are unknown at present. (Source: Gastroenterology)

Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case Study in Lynch Syndrome

Biometrics — Mon, 30 May 2011 23:00:00 +0100

Summary Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases. Its extent may vary between families and/or between mutation subtypes known to be associated with the disease phenotype. In this article, we posit a Bayesian approach to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO. Primary interest lies in the random effects. Misspecifying the distribution of random effects may result in incorrect inferential conclusions. We compare the fit of four‐candidate random effects distributions via Bayesian model fit diagnostics. A related statistical issue here is isolating the confounding e...

The liver: another organ involved in Muir Torre syndrome?

Familial Cancer — Wed, 25 May 2011 15:47:52 +0100

Abstract Muir Torre syndrome is a rare autosomal dominant cancer-predisposing syndrome characterized by the occurrence of sebaceous gland neoplasms and/or keratoacanthomas associated with visceral malignancies that belong to the spectrum of hereditary non polyposis colorectal cancer (HNPCC), i.e., tumors of gastrointestinal and genitourinary tracts. Hepatobiliary malignancy in association with Muir Torre syndrome has rarely been reported. Here, we describe a case of Muir Torre syndrome associated with an hepatocellular-carcinoma in a patient with a non-cirrhotic liver and an HNPCC-family with multiple cases of hepatocellular carcinoma. Content Type Journal ArticlePages 1-6DOI 10.1007/s10689-011-9450-1Authors F. Morando, Department of Clinical and Experimental Medicin...

Multimodality Treatment and Timing for Rectal Cancer in Hereditary Colorectal Cancer Patients

Seminars in Colon and Rectal Surgery — Fri, 20 May 2011 16:42:11 +0100

The management of rectal cancer is complex enough in itself but even more complicated in the setting of a hereditary cancer syndrome. Although the cancer treatment as such is similar to the one in sporadic cancer and based on cancer stage, tumor location, the patient's overall presentation and condition, the presence of an underlying disease raises additional concerns about functional aspects and the risk of metachronous lesions. We reviewed the role of multimodality treatment and the timing and extent of the planned surgeries. Rectal cancer in the setting of hereditary cancer syndromes (eg, hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis) is not genuinely handled with a different approach, except when an ileal pouch anal anastomosis is planned as the neo-adjuvant...

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Indication and Extent of Surgery in Hereditary Nonpolyposis Colorectal Cancer

Seminars in Colon and Rectal Surgery — Fri, 20 May 2011 16:42:10 +0100

This article reviews the literature to date regarding the extent of surgical resection, and addresses the approach to prophylactic measures to both colonic and gynecologic aspects of malignancy in hereditary nonpolyposis colorectal cancer. (Source: Seminars in Colon and Rectal Surgery)

Pathology and Immunohistochemistry of Hereditary Colorectal Cancer

Seminars in Colon and Rectal Surgery — Fri, 20 May 2011 16:42:09 +0100

Hereditary colorectal adenocarcinomas only represent a small proportion of all colorectal cancers and, of those, only a fraction have distinct clinical or pathologic features and a mutation of a gene associated with a hereditary syndrome. These hereditary conditions include hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MUTYH-associated polyposis, Peutz–Jeghers syndrome, and juvenile polyposis syndrome. Histopathologic features in patients with colorectal lesions (polyps, adenocarcinoma) that suggest the presence of a hereditary condition include the number and type of polyps, the morphologic features of the colorectal carcinoma, and the presence of extracolonic lesions or tumors. In addition, immunohistochemical stains can assist in identifying patients with ...

Epidemiology of Inherited Colon Cancer

Seminars in Colon and Rectal Surgery — Fri, 20 May 2011 16:42:09 +0100

Inherited colorectal cancer (CRC) represents 15-30% of all CRC cases. Hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis are the 2 main syndromes that comprise this category, and both have a well-defined genetic defect. The introduction of immunohistochemistry and genetic testing has resulted in earlier and more sensitive diagnosis of these hereditary syndromes. The incidence of hereditary nonpolyposis colorectal cancer is estimated at 2-5% of all CRC cases and is due to a mutation of the DNA mismatch repair genes. Familial adenomatous polyposis comprises 1% of all CRC cases and is caused by a mutation in the APC tumor suppressor gene. Familial X CRC syndrome contains the remainder of the inherited CRC cases (10-25% of all CRC cases) and encompasses patients who c...

Nonfamilial Adenomatous Polyposis/Nonhereditary Nonpolyposis Colorectal Cancer Hereditary Polyposis and Cancer Syndromes (MAP, Syndrome-X, Muir-Torre, etc)

Seminars in Colon and Rectal Surgery — Fri, 20 May 2011 16:42:09 +0100

Lynch syndrome and familial adenomatous polyposis represent the large majority of hereditary colorectal cancers; however, several additional less common syndromes are also associated with increased risk for developing malignancy. Identification of these syndromes requires an understanding of the phenotype to recognize the disease. Proper management of individuals and families affected by these syndromes provides an opportunity for cancer prevention. The purpose of this article is to provide a concise overview of the hereditary polyposis and colorectal cancer syndromes, exclusive of familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. (Source: Seminars in Colon and Rectal Surgery)

Screening and Surveillance Strategies in Hereditary Colon and Rectal Cancer

Seminars in Colon and Rectal Surgery — Fri, 20 May 2011 16:42:09 +0100

This article reviews the guidelines and analyzes the cost-effectiveness and possible obstacles for the 2 most common cancer syndromes, hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis. (Source: Seminars in Colon and Rectal Surgery)

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Polypoid adenocarcinoma of small bowel in a patient with hereditary nonpolyposis colorectal cancer: does an adjacent gastrojejunostomy have any influence on its development?

International Journal of Colorectal Disease — Tue, 10 May 2011 06:03:41 +0100

Content Type Journal ArticlePages 1-2DOI 10.1007/s00384-011-1224-6Authors Jaime Ruiz-Tovar, Department of General and Digestive Surgery, General University Hospital Elche, Alicante, SpainJavier Lacueva, Department of General and Digestive Surgery, General University Hospital Elche, Alicante, SpainIsrael Oliver, Department of General and Digestive Surgery, General University Hospital Elche, Alicante, SpainAmparo Martinez, Department of General and Digestive Surgery, General University Hospital Elche, Alicante, SpainRafael Calpena, Department of General and Digestive Surgery, General University Hospital Elche, Alicante, Spain Journal International Journal of Colorectal DiseaseOnline ISSN 1432-1262Print ISSN 0179-1958 (Source: International Journal of Colorectal Disease)

Glioblastoma multiforme in the Muir–Torre syndrome

Clinical Neurology and Neurosurgery — Tue, 10 May 2011 01:03:00 +0100

In this report, we describe the development of a glioblastoma multiforme (GBM) in a patient with MTS. Immunohistochemical analysis of the patient's colon carcinoma and his GBM both revealed loss of the mismatch repair proteins mutS homolog 2 (MSH2) and mutS homolog 6 (MSH6). (Source: Clinical Neurology and Neurosurgery)

Cyclin D1 G870A polymorphism and colorectal cancer susceptibility: a meta-analysis of 20 populations

International Journal of Colorectal Disease — Wed, 04 May 2011 14:55:14 +0100

Conclusion Result suggests that the cyclin D1 870A allele is a low-penetrant risk factor for developing sporadic colorectal cancer, especially among Caucasians. Content Type Journal ArticlePages 1-7DOI 10.1007/s00384-011-1220-xAuthors Lou-Qian Zhang, Department of Medical Oncology, Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, ChinaJun Wang, Department of Oncology, Geriatric Institution of Jiangsu Province, Nanjing, ChinaJun-Qing Shang, Department of Colorectal and Anal Surgery, Cancer Hospital of Jiangsu Province, Nanjing, ChinaJian-ling Bai, Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, ChinaFu-Yin Liu, Department of Oncology, Geriatric Institution of Jiangsu Province, Nanjing, ChinaXi...

A cost-effectiveness analysis of prophylactic surgery versus gynecologic surveillance for women from hereditary non-polyposis colorectal cancer (HNPCC) Families

Familial Cancer — Tue, 03 May 2011 05:56:09 +0100

This study investigates the cost-effectiveness of prophylactic surgery versus surveillance in women with Lynch Syndrome. A decision analytic model was designed incorporating key clinical decisions and existing probabilities, costs, and outcomes from the literature. Clinical forum where risk-reducing surgery and surveillance were considered. A theoretical population of women with Lynch Syndrome at age 30 was used for the analysis. A decision analytic model was designed comparing the health outcomes of prophylactic hysterectomy with bilateral salpingo-oophorectomy at age 30 versus annual gynecologic screening versus annual gynecologic exam. The literature was searched for probabilities of different health outcomes, results of screening modalities, and costs of cancer diagnosis and tre...

Recent progress in the diagnosis and treatment of ovarian cancer.

Clinical Colorectal Cancer — Sat, 30 Apr 2011 23:00:00 +0100

Authors: Jelovac D, Armstrong DK Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Screening strategies using ultrasound and the cancer antigen (CA) 125 tumor marker are currently under study and may lower stage at diagnosis but have not yet been shown to improve survival. Women who have inherited a deleterious mutation in the BRCA1 or BRCA2 gene and those with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have the highest risk of developing ovarian cancer but account for only approximately 10% of those with the disease. Other less common and less well-defined genetic syndromes may increase the risk of ovarian cancer, but their contribution to genetic risk is small. A clear eti...

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Distinct mutations in MLH1 and MSH2 genes in Hereditary Non-polyposis Colorectal Cancer (HNPCC) families from China.

BMB Reports — Sat, 30 Apr 2011 23:00:00 +0100

Authors: Wei W, Liu F, Liu L, Li Z, Zhang X, Jiang F, Shi Q, Zhou X, Sheng W, Cai S, Li X, Xu Y, Nan P Hereditary non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inheritance syndrome. HNPCC is the most common hereditary variant of colorectal cancer (CRC), which accounts for 2-5% CRCs, mainly due to hMLH1 and hMSH2 mutations that impair DNA repair functions. Our study aimed to identify the patterns of hMSH2 and hMLH1 mutations in Chinese HNPCC patients. Ninety-eight unrelated families from China meeting Amsterdam or Bethesda criteria were included in our study. Germline mutations in MLH1 and MSH2 genes, located in the exons and the splice-site junctions, were screened in the 98 probands by direct sequencing. Eleven mutations were found in ten patients (11%), with six in...

Deficiency in DNA mismatch repair increases the rate of telomere‐shortening in normal human cells

Human Mutation — Wed, 27 Apr 2011 23:00:00 +0100

In this study we show that there is a high level of instability within telomeric DNA with a tendency towards deletions in tumour derived MMR defective cell lines. We down‐regulated MSH2 expression in a normal fibroblast cell line and isolated four clones, with differing levels of MSH2 depletion. The telomere‐shortening rate was measured at the Xp/Yp, 12q and 17p telomeres in the MSH2 depleted and three control clones. Interestingly the mean telomere‐shortening rate in the clones with MSH2 depletion was significantly greater than in the control clones. This is the first demonstration that MSH2 deficiency alone can lead to accelerated telomere shortening in normal human cells. © 2011 Wiley‐Liss, Inc. (Source: Human Mutation)

Understanding Patterns of Health Communication in Families at Risk for Hereditary Nonpolyposis Colorectal Cancer: Examining the Effect of Conclusive Versus Indeterminate Genetic Test Results

Health Communication — Wed, 20 Apr 2011 11:44:53 +0100

(Source: Health Communication)

A two-antibody mismatch repair protein immunohistochemistry screening approach for colorectal carcinomas, skin sebaceous tumors, and gynecologic tract carcinomas

Modern Pathology AOP — Thu, 14 Apr 2011 23:00:00 +0100

Authors: Amirkaveh Mojtahed, Iris Schrijver, James M Ford, Teri A Longacre & Reetesh K Pai (Source: Modern Pathology AOP)

Le syndrome HNPCC (hereditary non polyposis colorectal cancer) ou syndrome de Lynch : un syndrome en rapport avec une défaillance du système de réparation de l'ADN.

Annales de Biologie Clinique — Sat, 02 Apr 2011 23:00:00 +0100

Authors: Manceau G, Karoui M, Charachon A, Delchier JC, Sobhani I The HNPCC syndrome (hereditary non polyposis colon cancer) or Lynch syndrome stands for an autosomic dominant condition leading to the most prevalent hereditary colo-rectal cancers (CCR). MMR (mismatch repair)'s genes are involved in carcinogenesis as they play a role in ADNA mismatch repair. Microsatellite instability (MSI+ phenotype) induced by germline mutations is characteristic of such tumors and is necessary to assert the diagnosis. The HNPCC syndrome is associated with a significant increased risk of CCR altogether with endometrium, upper urinary tract and small bowel carcinomas as well as ovarian, biliary system and gastric cancers although of lesser extent. It is of importance to diagnose HNPCC syndrome prior to...

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Utilité de l'immuno-histochimie dans la détection des altérations des gènes réparateurs des mésappariements de l'ADN À propos d'une série de 48 cas de cancers colorectaux.

Annales de Biologie Clinique — Thu, 31 Mar 2011 23:00:00 +0100

In conclusion, our study support the potential utility of immunohistochemistry to identify a significant portion of colorectal tumors derived from germline mutation of MMR genes and can be used as an adjunct measure in the identification of HNPCC. PMID: 21464009 [PubMed - as supplied by publisher] (Source: Annales de Biologie Clinique)

How Helpful Is Age at Colorectal Cancer Onset in Finding Hereditary Nonpolyposis Colorectal Cancer?

Clinical Gastroenterology and Hepatology — Fri, 25 Mar 2011 00:00:00 +0100

At least 1% to 3% of all colorectal cancers (CRCs) are known to be caused by mutations in one of the mismatch repair (MMR) genes responsible for hereditary nonpolyposis colorectal cancer (HNPCC, or Lynch syndrome). Although thus uncommon, the presence of HNPCC carries significant clinical management implications for the affected individual and for their relatives. However, the ability to detect the presence of HNPCC is relatively new, technically demanding, and complicated. These considerations make the undertaking to detect HNPCC challenging to the point of being off-putting to many clinical gastroenterologists and other providers. (Source: Clinical Gastroenterology and Hepatology)

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies

Familial Cancer — Mon, 14 Mar 2011 16:54:02 +0100

We report here all 88 MLH1 missense variants identified in families from the German HNPCC consortium with clinical details of these patients/families. We investigated 23 MLH1 missense variants by two functional in vivo assays in yeast; seven map to the ATPase and 16 to the protein interaction domain. In the yeast-2-hybrid (Y2H) assay three variants in the ATPase and twelve variants in the interaction domain showed no or a reduced interaction with PMS2; seven showed a normal and one a significantly higher interaction. Using the Lys2A 14 reporter system to study the dominant negative mutator effect (DNE), 16 variants showed no or a low mutator effect, suggesting that these are nonfunctional, three were intermediate and four wild type in this assay. The DNE and Y2H results were concor...

172 investigating the risk of bladder cancer among hereditary non-polyposis colorectal cancer (hnpcc) patients with confirmed mismatch repair (mmr) gene mutations

European Urology Supplements — Tue, 01 Mar 2011 00:00:00 +0100

(Source: European Urology Supplements)

Recent progress in the diagnosis and treatment of ovarian cancer

CA: A Cancer Journal for Clinicians — Tue, 01 Mar 2011 00:00:00 +0100

AbstractEpithelial ovarian cancer is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Screening strategies using ultrasound and the cancer antigen (CA) 125 tumor marker are currently under study and may lower stage at diagnosis but have not yet been shown to improve survival. Women who have inherited a deleterious mutation in the BRCA1 or BRCA2 gene and those with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have the highest risk of developing ovarian cancer but account for only approximately 10% of those with the disease. Other less common and less well‐defined genetic syndromes may increase the risk of ovarian cancer, but their contribution to genetic risk is small. A clear etiology for sporadic ovarian ...

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Prophylactic surgery in Lynch syndrome

Techniques in Coloproctology — Thu, 03 Feb 2011 07:23:52 +0100

Abstract Lynch syndrome (LS) is caused by a germline mutations in DNA mismatch repair genes and is a dominantly inherited syndrome, responsible for 2–5% of all colorectal cancer (CRC) cases. Mutation carriers have a 60–85% risk of developing CRC. With the increasing use of genetic predisposition testing, patients and health care providers must decide on cancer risk-reduction strategies. The cancers observed in families with LS are diagnosed at an unusually early age and may be multiple. The decision about which surgery is suitable should be made on the basis of patient factors and preferences, with special emphasis on age, comorbidity, sphincteric function, and the ability of the patient to cope with intensive surveillance. Colectomy decreases the risk of second CRC si...

Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation

Familial Cancer — Tue, 01 Feb 2011 08:49:39 +0100

Abstract Lynch syndrome (LS), or hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant condition responsible for early onset cancer mostly in the colonrectum and endometrium as well as in other organ sites. Lynch syndrome is caused by germline mutations in mismatch repair genes, prevalently in hMSH2, hMLH1, and less frequently in hMSH6 and hPMS2. Twenty-nine non-related index cases with colorectal cancer (CRC) were collected from a region in southeast Italy (Apulia). Among this set of patients, fifteen fulfilled the Amsterdam criteria II. The presence of tumor microsatellite instability (MSI) was assessed in all index cases and 19 (15 AC+/4 AC−) were classified as MSI-H. Mutation analysis performed on all patients, identified 15 pathogenic mutation...

Biomedical informatics as support to individual healthcare in hereditary colon cancer: the Danish HNPCC system

Human Mutation — Tue, 25 Jan 2011 00:00:00 +0100

AbstractThe Danish HNPCC register is a publically financed national database. The register gathers epidemiological and genomic data in HNPCC families to improve prognosis by screening and identifying family members at risk. Diagnostic data are generated throughout the country and collected over several decades. Until recently, paper‐based reports were sent to the register and typed into the database. In the EC cofunded‐INFOBIOMED network of excellence, the register was a model for electronic exchange of epidemiological and genomic data between diagnosing/treating departments and the central database. The aim of digitization was to optimize the organization of screening by facilitating combination of genotype–phenotype information, and to generate IT‐tools sufficiently usable and ge...

First evidence for digenic inheritance in hereditary colorectal cancer by mutations in the base excision repair genes

European Journal of Cancer — Mon, 03 Jan 2011 00:00:00 +0100

We describe here the first pathogenic germline mutation in OGG1, a splice site mutation affecting exon 1, which was inherited from the father, in combination with a maternal MUTYH missense mutation p.Ile223Val in a female patient with advanced synchronous colon cancer and adenomas at the age of 36years pointing towards digenic inheritance for colorectal cancer (CRC) predisposition.Monoallelic missense mutations in MTH1 (3x), OGG1 (2x), or MUTYH (3x) were identified in 10 patients (12%), three of them were novel.Our findings indicate that mutations in other genes of the 8-oxo-G repair beside MUTYH are involved in CRC predisposition. Oligogenic inheritance affecting genes of a certain repair pathway might therefore be the missing link between monogenic and polygenic traits. (Source: European...

Image-enhanced endoscopy

Techniques in Gastrointestinal Endoscopy — Sat, 01 Jan 2011 00:00:00 +0100

White light endoscopy is a basic tool available to gastroenterologists since the early 1960s, when flexible endoscopy was first introduced. Since then, gastroenterologists have been able to diagnose and treat gastrointestinal diseases at earlier stages. However, recent studies have also highlighted the limitations and imperfect nature of white light endoscopy. Image-enhanced endoscopy (IEE) has been available for the past 10 years and has been validated by research and clinical trials. A specific combination of dye-based (Lugol's solution, indigo carmine) and equipment-based IEE (narrow band imaging, Fujinon Intelligence Color Enhancement, Pentax i-Scan) is indicated for use in the oropharynx, hypopharynx, esophagus, stomach, and colon. The main use is for detecting, diagnosing, and treati...

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Familial gastric cancer: update for practice management

Familial Cancer — Thu, 23 Dec 2010 18:01:27 +0100

Abstract About 90% of gastric carcinoma presents a sporadic setting and only 10% shows a familial cluster; among this group, 1–3% are considered as hereditary syndromes, with a clear genetic pathway. The most important genetic mechanisms are associated with CDH1 germline mutations, causing the hereditary diffuse gastric cancer syndrome. Other inherited predispositions with gastric carcinoma are the hereditary nonpolyposis colorectal cancer, Li-Fraumeni and Peutz-Jeghers syndromes. In this brief update, we described these principal hereditary syndromes offering a simple management to physicians where are these diseases diagnosed. Content Type Journal ArticleDOI 10.1007/s10689-010-9410-1Authors Giovanni Corso, Department of Human Pathology and Oncology, Section of Gen...

[Lynch syndrome: genetics and surgery.]

Cirugia eEspanola — Mon, 20 Dec 2010 00:00:00 +0100

Authors: Ferrer Márquez M, Reina Duarte A, Maturana Ibáñez V, Belda Lozano R, Rubio Gil F, Blesa Sierra I, Del Mar Rico Morales M Hereditary nonpolyposis colorectal cancer or Lynch Syndrome, caused by germinal mutations in mismatch deoxyribonucleic acid (DNA) repair genes, is the most common form of hereditary colorectal cancer. The identification of these individuals is not easy and is based on clinical and molecular criteria. A review is presented on the genetics and diagnosis in Lynch Syndrome, as well as on its surgical management and prevention. PMID: 21176896 [PubMed - as supplied by publisher] (Source: Cirugia eEspanola)

Intensity‐dependent constitutional MLH1 promoter methylation leads to early onset of colorectal cancer by affecting both alleles

Genes, Chromosomes and Cancer — Fri, 10 Dec 2010 14:23:16 +0100

AbstractConstitutional epimutation is one of the causes for MLH1 gene inactivation associated with hereditary non‐polyposis colon cancer (HNPCC) syndrome. Here we investigate MLH1 promoter hypermethylation in 110 sporadic early‐onset colorectal cancer patients. Variable levels of hypermethylation were detected in 55 patients (50%). Importantly a reduced MLH1 gene expression was found in patients with high‐level methylation, with the association of microsatellite instability (MSI) in their tumor cells. Such high‐level methylation accounts for 7.4% of all patients included in this study. Furthermore, we found that in one case constitutional methylation affected both alleles, indicating a post‐zygotic methylation dysregulation. Our findings suggest that constitutional epimutation is...

Deranged Wnt signaling is frequent in hereditary nonpolyposis colorectal cancer

Familial Cancer — Mon, 06 Dec 2010 15:08:39 +0100

Abstract The Wnt signaling pathway is frequently deranged in colorectal cancer and is a key target for future preventive and therapeutic approaches. Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome are characterized by wide-spread microsatellite instability, but show few gross genomic alterations. We characterized expression of the Wnt signaling pathway markers β-catenin, E-cadherin, TCF-4, and PTEN using immunohistochemical staining in colorectal cancers from individuals with HNPCC. Reduced membranous staining for β-catenin was found in 64% and for E-cadherin in 80% with strong correlation between these markers (P = 0.001). Nuclear β-catenin staining was detected in 19% of the tumors. Overexpression of TCF-4, wh...

Racial differences in mlh1 and msh2 mutation: an analysis of yellow race and white race based on the insight database.

Journal of Bioinformatics and Computational Biology — Wed, 01 Dec 2010 00:00:00 +0100

RACIAL DIFFERENCES IN MLH1 AND MSH2 MUTATION: AN ANALYSIS OF YELLOW RACE AND WHITE RACE BASED ON THE INSIGHT DATABASE. J Bioinform Comput Biol. 2010 Dec;8(supp01):111-125 Authors: Wei W, Liu L, Chen J, Jin K, Jiang F, Liu F, Fan R, Cheng Z, Shen M, Xue C, Cai S, Xu Y, Nan P MLH1 and MSH2 mutations underlie 90% of hereditary nonpolyposis colorectal cancer (HNPCC) mutations. The International Society of Gastrointestinal Hereditary Tumors (InSiGHT) has established an international database of mutations associated with HNPCC. Based on the InSiGHT database and the original references that reported the mutations, we analyzed the distributions of MLH1 and MSH2 mutations in yellow race and white race respectively and compared them subsequently. We found: (1) the distributions of mutati...

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Leiomyosarcoma of the Oesophagus and Gastric Adenocarcinoma with Family History of HNPCC Syndrome.

Zentralblatt fur Chirurgie — Wed, 03 Nov 2010 00:00:00 +0100

Authors: Köhler K, Stelzner S, Haroske G, Witzigmann H PMID: 21049402 [PubMed - as supplied by publisher] (Source: Zentralblatt fur Chirurgie)

Microsatellite Instability Detection by High-Resolution Melting Analysis [Molecular Diagnostics and Genetics]

Clinical Chemistry — Wed, 27 Oct 2010 23:00:00 +0100

CONCLUSIONS: We expanded the application of the HRM analysis method as an effective MSI detection technique for clinical samples. (Source: Clinical Chemistry)

Microsatellite Instability (MSI) as Genomic Markers in Endometrial Cancer: Toward Scientific Evidences.

Mini Reviews in Medicinal Chemistry — Sun, 17 Oct 2010 18:20:13 +0100

Authors: Tinelli A, Mezzolla V, Leo G, Pisanò M, Storelli F, Alemanno G, Malvasi A, Ronzino G, Lorusso V Endometrial Cancer is the most frequent tumor in western world nations, with 142,000 new cases each year and 42,000 casualties. This form of cancer typically affects women between 55 and 65 years of age, and ranks fourth among female tumors. Endogenous predisposing conditions to endometrial cancer development are: late menopause, early menarche and hyperestrogenism, while hormone replacement therapy, obesity, alcohol, diabetes, and a diet rich in animal fats as well as chronic liver disease, are the exogenous factors. This tumor may also have an hereditary predisposition, as in the Lynch Syndrome or in HNPCC (Hereditary NonPolyposis Colorectal Cancer), since genetic modifications i...

Three novel germline mutations in MLH1 and MSH2 in families with Lynch syndrome living on Jeju island, Korea.

BMB Reports — Fri, 01 Oct 2010 00:00:00 +0100

Authors: Kim YM, Choe CG, Cho SK, Jung IH, Chang WY, Cho M Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterized by predisposition to early-onset cancers. HNPCC is caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6, PMS1, and PMS2. We genotyped the MLH1 and MSH2 genes in patients suffering from Lynch syndrome and in 11 unrelated patients who were diagnosed with colorectal cancer and had subsequently undergone surgery. Five Lynch syndrome patients carried germline mutations in MLH1 or MSH2. Two of these were identified as known mutations in MLH1: deletion of exon 10 and a point mutation (V384D). The remaining three patients exhibited novel mutations: a duplication (937_942dupGAAGTT) in MLH1; de...

Surgery for colonic cancer in HNPCC: Total versus segmental colectomy

Colorectal Disease — Thu, 30 Sep 2010 23:00:00 +0100

Abstract (Source: Colorectal Disease)

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Reassessing the TARBP2 mutation rate in hereditary nonpolyposis colorectal cancer

Nature Genetics — Wed, 29 Sep 2010 19:19:45 +0100

Authors: Pilar Garre, Pedro Pérez-Segura, Eduardo Díaz-Rubio, Trinidad Caldés & Miguel de la Hoya (Source: Nature Genetics)

Reply to “Reassessing the TARBP2 mutation rate in hereditary nonpolyposis colorectal cancer”

Nature Genetics — Wed, 29 Sep 2010 19:19:45 +0100

Reply to “Reassessing the TARBP2 mutation rate in hereditary nonpolyposis colorectal cancer” Nature Genetics 42, 818 (2010). doi:10.1038/ng1010-818 Authors: Sonia A Melo & Manel Esteller (Source: Nature Genetics)

Germline Genetic Variation, Cancer Outcome, and Pharmacogenetics [REVIEW ARTICLES]

Journal of Clinical Oncology — Wed, 08 Sep 2010 22:00:49 +0100

Studies of the role of germline or inherited genetic variation on cancer outcome can fall into three distinct categories. First, the impact of highly penetrant but lowly prevalent mutations of germline DNA on cancer prognosis has been studied extensively for BRCA1 and BRCA2 mutations as well as mutations related to hereditary nonpolyposis colorectal cancer syndrome. These mainly modest-sized analyses have produced conflicting results. Although some associations have been observed, they may not be independent of other known clinical or molecular prognostic factors. Second, the impact of germline polymorphisms on cancer prognosis is a burgeoning field of research. However, a deeper understanding of potentially confounding somatic changes and larger multi-institutional, multistage studies may...

With HNPCC (Lynch Syndrome) Colon Cancer, Watch for Endometrial Cancer Too

About.com Colon Cancer — Sun, 29 Aug 2010 23:00:00 +0100

For anyone with Lynch syndrome, a comprehensive colon cancer screening plan is a must. By screening for colon cancer and receiving appropriate medical care for the condition, a person can greatly reduce his or her odds of dying of colon cancer. The cancers can be caught and removed early, when they are most treatable....Read Full Post (Source: About.com Colon Cancer)

An intronic mutation in MLH1 associated with familial colon and breast cancer

Familial Cancer — Tue, 17 Aug 2010 17:22:04 +0100

We describe an HNPCC patient, with early-onset colorectal cancer and a strong family history of colorectal and breast tumors, who harbours a germ line MLH1 intronic variant (IVS9 c.790 +4A>T). The proband, together with 2 relatives affected by colorectal-cancer and 1 by breast cancer, have been investigated for microsatellite instability, immunohistochemical MMR protein staining, direct sequencing and Multiplex Ligation-dependent Probe Amplification. The effect of the intronic variant was analyzed both by splicing prediction software and by hybrid minigene splicing assay. In this family, we found a novel MLH1 germline intronic variant (IVS9 c.790 +4A>T) in intron 9, consisting of an A to T transversion, in position +4 of the splice donor site of MLH1. The mutation is associated...

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Germline mutation analysis of hPMS2 gene in Chinese families with hereditary nonpolyposis colorectal cancer.

World Journal of Gastroenterology : WJG — Thu, 12 Aug 2010 17:42:11 +0100

CONCLUSION: The germline mutation of hPMS2 gene may be rare in Chinese HNPCC families. The 2nd and 5th exons are hot SNP regions of hPMS2 gene. PMID: 20698049 [PubMed - in process] (Source: World Journal of Gastroenterology : WJG)

Improved Testing for Microsatellite Instability in Colorectal Cancer Using a Simplified 3-Marker Assay

Annals of Surgical Oncology — Thu, 12 Aug 2010 06:03:56 +0100

Conclusion The 3-marker MSI assay outperforms the traditional 5-marker assay for identifying patients with favorable prognosis and homogeneous clinical and genetic features. More accurate MSI testing should improve prognostic and predictive scoring systems for colorectal cancer. Content Type Journal ArticleDOI 10.1245/s10434-010-1147-4Authors Iyare Esemuede, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY USAAnn Forslund, Department of Genetics, Albert Einstein College of Medicine, Bronx, NY USASajid A. Khan, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY USALi-Xuan Qin, Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY USAMark I. Gimbel, Department of Surgery, Memo...

Pre-operative Gynecologic Evaluation of Bariatric Surgery Patients: Improving Cancer Detection in a High-Risk Population

Journal of the American College of Surgeons — Fri, 30 Jul 2010 07:11:21 +0100

Conclusions: Given the massive increases in morbid obesity and bariatric surgery in women, surgeons could serve a vital role in educating patients about both gynecologic and nongynecologic malignancy risks. With appropriate referral for cancer screening, patient outcomes could improve. (Source: Journal of the American College of Surgeons)

Report From the Jerusalem Workshop on Lynch Syndrome-Hereditary Nonpolyposis Colorectal Cancer

Gastroenterology — Tue, 27 Jul 2010 05:44:17 +0100

NOTE. In June 2010 we published this meeting summary in print only (Gastroenterology 2010;139:2197-2201). In this issue we are now providing it online for our Internet readers. (Source: Gastroenterology)

NHS HTA - chemoprevention of colorectal cancer

NeLM - Disease Focused Reviews — Sun, 25 Jul 2010 23:00:00 +0100

Source: Health Technology Assessment Area: Evidence > Disease Focused Reviews This review examines the clinical and cost-effectiveness of micronutrient and pharmacological approaches for chemoprophylaxis of colorectal cancer. Colorectal cancer (CRC) is one of the most common cancers in the UK, and most tumours arise from adenomatous polyps arising from the intestine lining. Various interventions have been proposed to reduce the risk, and the assessment examined non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclo-oxygenase-2 (COX-2) inhibitors; folic acid; calcium; vitamin D and antioxidants (including vitamin A, vitamin C, vitamin E, selenium and beta-carotene). Chemoprevention was assessed in the general population, in individuals at increased risk of C...

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Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

Journal of Medical Genetics — Wed, 30 Jun 2010 08:15:30 +0100

Conclusion Patients with Lynch syndrome carrying an MSH2 mutation are at increased risk of urinary tract cancer including bladder cancer. In these cases surveillance should be considered. (Source: Journal of Medical Genetics)

Interobserver variability in the evaluation of mismatch repair protein immunostaining

Human Pathology — Tue, 22 Jun 2010 23:00:00 +0100

Summary: Immunohistochemical staining for mismatch repair proteins has during recent years been established as a routine analysis in many pathology laboratories with the aim to identify tumors linked to the hereditary nonpolyposis colorectal cancer syndrome. Despite widespread application, data on reliability are lacking. We therefore evaluated interobserver variability among 6 pathologists, 3 experienced gastrointestinal pathologists and 3 residents. In total, 225 immunohistochemically stained colorectal cancers were evaluated as having normal, weak, loss of, or nonevaluable mismatch repair protein staining. Full consensus was achieved in 51% of the stainings for MLH1, 61% for PMS2, 83% for MSH2, and 45% for MSH6. Weak stainings were the main cause of reduced consensus, whereas contradict...

Researchers' Work From Radboud University Focuses On Hereditary Nonpolyposis Colorectal Cancer

Cancercompass News: Colorectal Cancer — Fri, 18 Jun 2010 00:00:00 +0100

Fresh data on hereditary nonpolyposis colorectal cancer are presented in the report 'Electronic reminders for pathologists promote recognition of patients at risk for Lynch syndrome: cluster- randomised controlled trial.' According to recent research from Nijmegen, Netherlands, We investigated success factors for the introduction of a guideline on recognition of Lynch syndrome in patients recently diagnosed with colorectal cancer (CRC) below age 50 or a second CRC below age 70. (Source: Cancercompass News: Colorectal Cancer)

En bloc right hemicolectomy and pancreaticoduodenectomy for HNPCC with simultaneous mutations of MSH-2 and MSH-6

International Journal of Colorectal Disease — Thu, 17 Jun 2010 11:25:46 +0100

Content Type Journal ArticleCategory Letter to the EditorDOI 10.1007/s00384-010-0990-xAuthors Xavier M. Keutgen, New York Presbyterian Hospital–Weill Cornell Medical Center Division of Minimally Invasive and Endocrine Surgery, Department of Surgery 525 E. 68th Street New York NY 10065 USAFilippo Filicori, New York Presbyterian Hospital–Weill Cornell Medical Center Division of Minimally Invasive and Endocrine Surgery, Department of Surgery 525 E. 68th Street New York NY 10065 USASang W. Lee, New York Presbyterian Hospital–Weill Cornell Medical Center Division of Colorectal Surgery, Department of Surgery 525 E. 68th Street New York NY 10065 USARasa Zarnegar, New York Presbyterian Hospital–Weill Cornell Medical Center Division of Minimally Invasive and Endocrine Surgery, Departmen...

Hopefulness predicts resilience after hereditary colorectal cancer genetic testing: a prospective outcome trajectories study

BMC Cancer — Thu, 10 Jun 2010 23:00:00 +0100

Conclusions: The current findings suggest that hopefulness may predict resilience after HCRC genetic testing in Hong Kong Chinese. Interventions to increase the level of hope may be beneficial to the psychological adjustment of HCRC genetic testing recipients. (Source: BMC Cancer)

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Mucinous adenocarcinoma showing different clinicopathological and molecular characteristics in relation to different colorectal cancer subgroups

International Journal of Colorectal Disease — Mon, 07 Jun 2010 17:08:41 +0100

Conclusions Significantly different tumor localization was observed between mucinous YSCC (left colon predominance) and mucinous HNPCC (right colon predominance). Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00384-010-0958-xAuthors J. M. Chiang, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine Division of Colon and Rectal Surgery Lin-Kou TaiwanC. Y. Yeh, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine Division of Colon and Rectal Surgery Lin-Kou TaiwanC. R. Changchien, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine Division of Colon and Rectal Surgery Lin-Kou TaiwanJ. S. Chen, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine Division of ...

TCF-3, 4 protein expression correlates with β-catenin expression in MSS and MSI-H colorectal cancer from HNPCC patients but not in sporadic colorectal cancers

International Journal of Colorectal Disease — Mon, 07 Jun 2010 17:08:39 +0100

Conclusion We have shown a previously unknown difference in TCF-3, 4 protein expression between sporadic and HNPCC MSS tumors. In addition, we found no difference in nuclear β-catenin signal intensity, which may be caused by an alteration in Wnt pathway in MSS sporadic tumors by unknown mechanisms leading to lower TCF-3, 4 protein expression. This hypothesis has to be tested in future investigations. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00384-010-0959-9Authors Peter Balaz, Technische Universität Dresden Department of Surgical Research Fetscherstrasse 74 01307 Dresden GermanyJens Plaschke, Technische Universität Dresden Department of Surgical Research Fetscherstrasse 74 01307 Dresden GermanyStefan Krüger, Technische Universität Dresd...

MSI phenotype and MMR alterations in familial and sporadic gastric cancer

International Journal of Cancer — Sun, 06 Jun 2010 23:00:00 +0100

Microsatellite instability (MSI) is a major pathway involved in gastric carcinogenesis occurring in 20% of gastric cancer (GC). However, it is not clear whether MSI phenotype preferentially occurs in the sporadic or familial GC, when stringent inclusion criteria are used. The aim of this study was to compare the frequency of MSI and hypermethylation of MLH1 promoter in a large series of familial GC patients (non-HNPCC and non-CDH1-related) and sporadic cases. Additionally, we analysed the immunoexpression of MMR proteins in a fraction of cases. Overall, the frequency of familial GC was 7.1%, and the frequency of hereditary tumours was 4.6%. MSI phenotype and MLH1 hypermethylation frequencies were not statistical different between familial and sporadic GC settings. Further, the MSI phenotyp...

Latest updates to the CRD databases

Fri, 04 Jun 2010 13:16:55 +0100

The following resources were added to the databases from the Centre for Reviews and Dissemination during the last update: Added to DARE (these records are structured abstracts for published systematic reviews and meta-analyses): Biofeedback therapy in fecal incontinence and constipation Chiropractic spinal manipulation for infant colic: a systematic review of randomised clinical trials Diagnostic testing for celiac disease among patients with abdominal symptoms: a systematic review High-dose vs non-high-dose proton pump inhibitors after endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of randomized controlled trials Meta-analysis of endoscopic submucosal dissection versus endoscopic mucosal resection for tumors of the gastrointestinal tract...

[Correlation between microsatellite instability and morphology in colorectal cancer.]

Magyar Onkologia — Mon, 31 May 2010 23:00:00 +0100

Authors: Szentirmay Z, Gallai M, Serester O, Szoke J, TÃ³th E Microsatellite instability (MSI) influences the development and clinical course of colorectal cancers (CRCs) and induce specific morphological alterations of such neoplasms, therefore hematoxylin-eosin (H&E) based histology allows to predict the microsatellite status of a given tumor. The aim of this article is to demonstrate clinicopathological features that are useful in recognition of microsatellite-stable and -unstable CRCs on routine histological examination. In the Center of Surgical and Molecular Pathology of National Institute of Oncology, from 384 CRC cases 26 hereditary non-polyposis colorectal cancers (HNPCC), 22 sporadic high-level microsatellite-instable (MSI-H) cancers and 76 microsatellite-stable (MSS) o...

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[Correlation between microsatellite instability and morphology in colorectal cancer]

Magyar Onkologia — Mon, 31 May 2010 23:00:00 +0100

Microsatellite Instability (MSI) As Genomic Markers In Endometrial Cancer: Toward Scientific Evidences.

Mini Reviews in Medicinal Chemistry — Sun, 23 May 2010 23:00:00 +0100

Authors: Tinelli A, Mezzolla V, Leo G, PisanÃ M, Storelli F, Malvasi A, Ronzino G, Lorusso V Endometrial Cancer is the more frequent tumor in Occidental lands, with 142000 new cases for year and 42000 deaths; this cancer typically strikes women between 55 and 65 years and it is on the fourth place in female tumors. Endogen predisposing conditions to endometrial cancer development are: late menopause, early menarche and hyperestrogenism, while hormone replacement therapy, obesity, alcohol, diabetes, diet rich of animal fats and chronic liver disease represent exogenous factors. This tumor can arise even as hereditary predisposition, as in Lynch Syndrome or HNPCC (Hereditary NonPolyposis Colorectal Cancer), since the genetic modifications induced by "MisMatch Repair" genes lead to a t...

Colorectal cancers show distinct mutation spectra in members of the canonical WNT signaling pathway according to their anatomical location and type of genetic instability

Genes, Chromosomes and Cancer — Fri, 07 May 2010 23:00:00 +0100

In conclusion, the observed spectra of WNT gene mutations in colorectal tumors are likely the result from selection of specific levels of [beta]-catenin signaling, optimal for tumor formation in the context of specific anatomical locations and forms of genetic instability. We suggest that this may underlie the preferential location of MMR deficient tumors in the proximal colon. © 2010 Wiley-Liss, Inc. (Source: Genes, Chromosomes and Cancer)

CHEK2 mutations and HNPCC-related colorectal cancer.

Cancer Control — Fri, 07 May 2010 17:10:31 +0100

Authors: Suchy J, Cybulski C, WokoÅorczyk D, Oszurek O, GÃ³rski B, Debniak T, Jakubowska A, Gronwald J, Huzarski T, Byrski T, Dziuba I, Gogacz M, WiÅniowski R, Wandzel P, Banaszkiewicz Z, Kurzawski G, KÅadny J, Narod SA, LubiÅski J Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non-polyposis-colorectal cancer (HNPCC) and HNPCC-related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC-related families in Poland, we genotyped 463 probands from HNPCC and HNPCC-related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS2+1G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC-rela...

Report From the Jerusalem Workshop on Lynch Syndrome-Hereditary Nonpolyposis Colorectal Cancer

Gastroenterology — Wed, 21 Apr 2010 23:00:00 +0100

This study estimated the prevalence of detectable disease at 2.8% of all CRC and 2.5% of all endometrial cancer patients. Based on these prevalence figures, the lifetime risks for CRC (6%) and endometrial cancer (4%) in the general population, and the average penetrance of approximately 50%, he estimated that perhaps 1 in 300 to 1 in 500 individuals in the general population has Lynch syndrome. That would make Lynch syndrome the most common Mendelian genetic predisposition to cancer. He further reported that genetic screening of all CRC patients who meet the Amsterdam criteria would still fail to detect half of all cases; likewise, screening only those aged ≤50 would detect only half of all cases; and screening all patients using the Bethesda guidelines for microsatellite instability (MS...

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The genetic link

Kidney Cancer Association — Tue, 13 Apr 2010 12:49:09 +0100

HNPCC also raises the risk of other cancers, including ovarian, stomach, pancreatic and kidney cancer.04/13/2010 (Source: Kidney Cancer Association)

Endoscopic surveillance for hereditary non-polyposis colorectal cancer (HNPCC) family members in a Southern Italian region

Digestive and Liver Disease — Sun, 11 Apr 2010 23:00:00 +0100

Conclusions: Our data suggests that surveillance colonoscopy every 2 years is adequate to diagnose advanced lesions in HNPCC family members, and improves their compliance with surveillance. (Source: Digestive and Liver Disease)

New Colon Cancer Genetics Data Have Been Reported

Cancercompass News: Colorectal Cancer — Sat, 10 Apr 2010 00:00:00 +0100

Current study results from the report, 'Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4- antibody panel,' have been published. (Source: Cancercompass News: Colorectal Cancer)

Analysis of mismatch repair gene mutations in Turkish HNPCC patients

Familial Cancer — Tue, 06 Apr 2010 18:26:32 +0100

Abstract Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is caused by the inheritance of a mutant allele of a DNA mismatch repair gene. We aimed to investigate types and frequencies of mismatch repair (MMR) gene mutations in Turkish patients with HNPCC and to identify specific biomarkers for early diagnosis of their non-symptomatic kindred’s. The molecular characteristics of 28 Turkish colorectal cancer patients at high-risk for HNPCC were investigated by analysis of microsatellite instability (MSI), immunohistochemistry and methylation-specific PCR in order to select tumors for mutation analysis. Ten cases (35.7%) were classified as MSI (+). Lack of expression of the main MMR proteins was observed in MSI (+) tumors. Hypermethylation of the MLH1 prom...

1080b: Narrow Band Imaging (NBI) for Adenoma Detection in High Risk Patients: A Randomised, Controlled Trial

Gastrointestinal Endoscopy — Wed, 31 Mar 2010 23:00:00 +0100

Randomised data so far suggest that NBI provides limited or no benefit for adenoma detection at colonoscopy in patients at standard risk of adenomas[]; however a back-to-back study in high risk patients with hereditary non-polyposis colorectal cancer (HNPCC) did show improved adenoma detection[]. No randomised data exist for other higher risk groups where NBI might be more effective. (Source: Gastrointestinal Endoscopy)

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W1468: Aberrant Crypt Foci Identified In Vivo by Magnifying Chromoscopy in Subjects With Hereditary Non-Polyposis and First Degree Relatives

Gastrointestinal Endoscopy — Wed, 31 Mar 2010 23:00:00 +0100

Aberrant Crypt Foci (ACF) have histological and genetic features common to colorectal adenomas and are considered the earliest marker for colorectal cancer (CRC). However to date there are no in vivo studies showing prevalence, number, size, and dysplastic features of aberrant crypt foci and their distribution in subjects with HNPCC and first degree relatives. Our aim was to investigate the presence, density, topographical features and histology of ACF in subjects with HNPCC and sporadic CRC. (Source: Gastrointestinal Endoscopy)

Epimutations and cancer predisposition: importance and mechanisms.

Current Opinion in Genetics and Development — Tue, 30 Mar 2010 23:00:00 +0100

Authors: Hesson LB, Hitchins MP, Ward RL Germline sequence mutations in tumour suppressor genes can cause cancer predisposition syndromes. More recently, epimutations have also been proposed to cause at least one such syndrome, hereditary non-polyposis colorectal cancer (HNPCC). 'Epigenetic predisposition', is defined as an inherited propensity to an altered epigenetic state in normal tissues that confers a predisposition to disease. Genetic sequence variations acting in cis or trans may contribute to epigenetic variations. Understanding the origin of epimutations will inform cancer risk assessment and will also aid the design and application of new therapies that target the epigenome. PMID: 20359882 [PubMed - as supplied by publisher] (Source: Current Opinion in Genetics and Devel...

Mesalazine Reduces Mutations in Transforming Growth Factor {beta} Receptor II and Activin Type II Receptor by Improvement of Replication Fidelity in Mononucleotide Repeats.

Cell Research — Tue, 02 Mar 2010 00:00:00 +0100

CONCLUSIONS: 5-ASA increases replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats and reduces mutations in tumor suppressor genes TGFBR2 and ACVR2, a finding that may provoke in vivo studies for the prevention of colorectal cancer in hereditary nonpolyposis colorectal cancer. Clin Cancer Res; 16(6); 1950-6. PMID: 20197483 [PubMed - as supplied by publisher] (Source: Cell Research)

Recent Findings Highlight Research In Hereditary Nonpolyposis Colorectal Cancer

Cancercompass News: Colorectal Cancer — Fri, 26 Feb 2010 00:00:00 +0100

Of the estimated 150,000 colorectal cancer (CRC) cases diagnosed annually, approximately 30% have a familial basis and 3% to 5% are from high- penetrance inherited cancer syndromes. Lynch syndrome, or hereditary nonpolyposis colorectal cancer, caused by inherited germline mutations in mismatch repair (MMR) genes, is the most commonly inherited CRC syndrome, scientists in the United States report. (Source: Cancercompass News: Colorectal Cancer)

Reports from Cleveland Clinic Advance Knowledge In Colon Cancer

Cancercompass News: Colorectal Cancer — Fri, 26 Feb 2010 00:00:00 +0100

According to recent research published in the journal Diseases of the Colon & Rectum, Hereditary nonpolyposis colorectal cancer is a hereditary syndrome defined by personal and family history of colorectal and other cancers. Some patients with this condition have multiple serrated polyps, which are the hallmark of hyperplastic polyposis syndrome, a rare colorectal cancer syndrome characterized by multiple hyperplastic/serrated polyps and an increased risk of colorectal cancer. (Source: Cancercompass News: Colorectal Cancer)

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Annual Colonoscopy Helpful for High-Risk Cancer Group

Modern Medicine — Thu, 25 Feb 2010 00:00:00 +0100

Annual colonoscopies can provide timely detection of early-stage colorectal cancer in the high-risk group of people with the genetic condition known as hereditary nonpolyposis colorectal cancer, according to a study in the February issue of Clinical Gastroenterology and Hepatology. (Source: Modern Medicine)

Decision Model of Segmental Compared With Total Abdominal Colectomy for Colon Cancer in Hereditary Nonpolyposis Colorectal Cancer [Surgical Oncology]

Journal of Clinical Oncology — Wed, 24 Feb 2010 23:01:02 +0100

Conclusion SEG and TAC are approximately equivalent strategies for patients with colon cancer and Lynch syndrome. The decision regarding which operation is preferable should be made on the basis of patient factors and preferences, with special emphasis on age and the ability of the patient to utilize intensive surveillance. (Source: Journal of Clinical Oncology)

Explanations of Risk in Families Without Identified Mutations for Hereditary Nonpolyposis Colorectal Cancer

Journal of Nursing Scholarship — Wed, 24 Feb 2010 00:00:00 +0100

Conclusions: Members of families without identified HNPCC mutations vary in their explanations for, interpretations of, and responses to indeterminate genetic test results. Clinical Relevance: Explanations of family risk and interpretations of individual risk offer healthcare providers valuable information. In combination with the Awareness and Surveillance Trajectory, assessment of these beliefs can facilitate development of individualized recommendations and strategies for possible preventive actions. (Source: Journal of Nursing Scholarship)

Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds

Journal of Medical Genetics — Tue, 09 Feb 2010 15:17:06 +0100

Conclusions In the series examined, infiltrating ovarian cancer in Lynch syndrome had a better prognosis than infiltrating ovarian cancer in BRCA1/2 mutation carriers or in the general population. Lifetime risk of ovarian cancer of about 10% and a risk of dying of ovarian cancer of 20% gave a lifetime risk of dying of ovarian cancer of about 2% in female MMR mutation carriers. (Source: Journal of Medical Genetics)

Studies From University Of Cambridge, Department Of Pathology Have Provided New Information About Hereditary Nonpolyposis Colorectal Cancer

Cancercompass News: Colorectal Cancer — Thu, 04 Feb 2010 00:00:00 +0100

Fresh data on hereditary nonpolyposis colorectal cancer are presented in the report 'DNA mismatch repair deficiency in sporadic colorectal cancer and Lynch syndrome.' According to recent research published in the journal Histopathology, DNA mismatch repair (MMR) deficiency is one of the best understood forms of genetic instability in colorectal cancer (CRC), and is characterized by the loss of function of the MMR pathway. (Source: Cancercompass News: Colorectal Cancer)

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A ten markers panel provides a more accurate and complete microsatellite instability analysis in mismatch repair-deficient colorectal tumors.

Cancer Biomarkers : Section A of Disease Markers — Fri, 01 Jan 2010 00:00:00 +0100

Conclusion: a complete panel of ten markers including four dinucleotide and six mononucleotide microsatellites allows accurate evaluation of tumor MSI status. PMID: 20164541 [PubMed - in process] (Source: Cancer Biomarkers : Section A of Disease Markers)

R659X mutation in the MLH1 gene in hereditary non-polyposis colorectal cancer(HNPCC) in an Indian extended family.

Indian J Med Res — Fri, 01 Jan 2010 00:00:00 +0100

CONCLUSION: R659X mutation correlates with disease phenotype, and 655A>G locus is highly polymorphic. Our study suggested that R659X substitution was prime cause for the disease phenotype in this family. I219V substitution is a polymorphism having no association with the disease onset or segregation. The family members harbouring this mutation were advised to be under regular medical surveillance. PMID: 20167975 [PubMed - in process] (Source: Indian J Med Res)

[Clinical and pathological analysis of 8 hereditary nonpolyposis colorectal cancer pedigrees.]

Journal of Southern Medical University — Sun, 20 Dec 2009 00:00:00 +0100

Authors: Wang Y, Yang L, Ding YQ, Tong J OBJECTIVE: To analyze the clinical and pathological features of patients with hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: The data of 8 HNPCC pedigrees according with Amsterdam standard II were collected and their pedigree trees were generated. RESULTS: The morbidity of HNPCC was 1.59%. Thirty-one patients were found in the 8 HNPCC pedigrees including 25 with colorectal cancer and 6 with extraintestinal tumors. The 8 prohands consisted of 6 female and 2 male patients, among whom 4 were younger than 40 years old, 2 had lesions in the right colon, 3 in the left colon, and 3 in the rectum. The tumors were histologically identified mainly as highly to modeerately differentiated adenocarcinoma; all the patients were free of lymph node...

Mismatch Repair Gene: The Underlying Defect of Hereditary Nonpolyposis Colorectal Cancer Syndrome

Advances in Anatomic Pathology — Fri, 18 Dec 2009 14:54:53 +0100

No abstract available (Source: Advances in Anatomic Pathology)

Scientists At Ohio State University, Medical Department Target Hereditary Nonpolyposis Colorectal Cancer

Cancercompass News: Colorectal Cancer — Fri, 18 Dec 2009 00:00:00 +0100

According to recent research from the United States, Currently, three prediction models are used to predict a patient's risk of having Lynch syndrome (LS). These models have been validated in probands with colorectal cancer (CRC), but not in probands presenting with endometrial cancer (EMC). (Source: Cancercompass News: Colorectal Cancer)

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A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1

Human Mutation — Thu, 17 Dec 2009 00:00:00 +0100

The hereditary colon and endometrium cancer predisposition Lynch Syndrome (also called HNPCC) is caused by a germ-line mutation in one of the DNA mismatch repair (MMR) genes. A significant fraction of the gene alterations detected in suspected Lynch Syndrome patients is comprised of amino acid substitutions. The relevance for cancer risk of these variants is difficult to assess, as currently no time- and cost-effective, validated, and widely applicable functional assays for the measurement of MMR activity are available. Here we describe a rapid, cell-free, and easily quantifiable MMR activity assay for the diagnostic assessment of variants of the MLH1 MMR protein. This assay allows the parallel generation and functional analysis of a series of variants of the MLH1 protein in vitro using re...

Three synchronous primary carcinomas in a patient with HNPCC associated with a novel germline mutation in MLH1: Case report

World Journal of Surgical Oncology — Tue, 08 Dec 2009 00:00:00 +0100

Conclusions: Our case demonstrates that HNPCC patients with MLH1 mutations are also at risk for ureteral neoplasms, and therefore urological surveillance is essential. This case adds to the growing list of disease-causing MMR mutations, and contributes to the development of genotype-phenotype correlations essential for assessing individual cancer risk and tailoring of optimal surveillance strategies. Additionally, our case draws attention to limitations of the Amsterdam Criteria and the need to maintain a high index of suspicion when newly diagnosed colorectal cancer meets the Bethesda Criteria. Establishment of the diagnosis is the crucial first step in initiating appropriate surveillance for colorectal cancer and other HNPCC-associated tumors in at-risk individuals. (Source: World Journa...

Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer

Journal of Medical Genetics — Tue, 01 Dec 2009 18:04:20 +0100

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterised by a predisposition to early onset colorectal, endometrial and other cancers. The tumours typically exhibit microsatellite instability due to defective mismatch repair. HNPCC is classically caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6 and PMS2, but no pathogenic mutations are identified in a third of cases. In recent years, constitutional epimutations of the MLH1 gene, characterised by soma-wide allele specific promoter methylation and transcriptional silencing, have been identified in a handful of mutation negative HNPCC cases. In contrast to genetic mutations, MLH1 epimutations are reversible between generations and thus display non-Men...

Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

BioMed Central — Fri, 20 Nov 2009 00:00:00 +0100

Conclusion: LGRs accounted for 25% of germline MMR mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the MSH2 mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the MLH1 or MSH2 gene (heterozygous LGR region, SNP, or microsatellite) is a novel finding and can be regarded as a partial LOH. The conversion begins within the gene, and the details of conversion tracts are discussed for each case. (Source: BioMed Central)

Inherited Colorectal Cancer Syndromes

Clinics in Colon and Rectal Surgery — Sat, 07 Nov 2009 15:13:38 +0100

Clinics in Colon and Rectal Surgery 2009; 22: 198-208DOI: 10.1055/s-0029-1242459ABSTRACTColorectal cancer is common in the Western world; ~5% of individuals diagnosed with colorectal cancer have an identifiable inherited genetic predisposition to this malignancy. Genetic testing and rational clinical management recommendations currently exist for the management of individuals with a variety of colorectal cancer syndromes, including hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), familial adenomatous polyposis (FAP), MYH-associated polyposis (MAP), and the hamartomatous polyposis syndromes (Peutz–Jeghers, juvenile polyposis, and Cowden disease). In addition to colorectal neoplasia, these syndromes frequently predispose carriers to a variety of extracol...

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Assessing pathogenicity of MLH1 variants by co-expression of human MLH1 and PMS2 genes in yeast

BMC Cancer — Wed, 28 Oct 2009 00:00:00 +0100

Conclusions: Results of our in vivo yeast-based approach correlate well with clinical data in five out of seven hMLH1 variants and the described model was thus shown to be useful for functional characterization of MLH1 variants in cancer patients found throughout the entire coding region of the gene. (Source: BMC Cancer)

CHEK2 mutations and HNPCC-related colorectal cancer

International Journal of Cancer — Wed, 28 Oct 2009 00:00:00 +0100

Recently, the 1100delC variant of cell cycle checkpoint kinase 2 (CHEK2) has been reported to confer a colorectal cancer risk in hereditary non-polyposis-colorectal cancer (HNPCC) and HNPCC-related families in the Netherlands. To investigate whether CHEK2 mutations confer increased cancer risk in HNPCC and HNPCC-related families in Poland, we genotyped 463 probands from HNPCC and HNPCC-related families, and 5,496 controls for 4 CHEK2 alleles (1100delC, IVS2+1G>A, del5395, I157T). All 463 probands were screened for mutations in the HNPCC-related genes MSH2, MLH1 and MSH6. A positive association was observed for HNPCC-related cancer and the I157T missense CHEK2 mutation (OR = 1.7; p = 0.007), but not for the truncating alleles (OR = 1.0; p = 1.0). The association with the I157T was seen both...

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC

Familial Cancer — Thu, 22 Oct 2009 19:00:52 +0100

In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC amon...

Review of family history taking in women aged under fifty years presenting with colorectal cancer

European Journal of Surgical Oncology — Fri, 16 Oct 2009 12:46:53 +0100

Introduction: Colorectal Cancer is a leading cause of mortality in the UK, with an average age of diagnosis of 64 years. HNPCC is a genetic condition caused by germline mutations in DNA mismatch repair gene, manifesting as an 80% lifetime risk of developing colorectal cancer with an average age of diagnosis of 44 years. HNPCC also signifies an increased risk of other cancers including endometrial, ovarian, small bowel, ureter and stomach. It is therefore relevant for a comprehensive family history to be elicited in women (Source: European Journal of Surgical Oncology)

Efficacy of Annual Colonoscopic Surveillance in Individuals With Hereditary Nonpolyposis Colorectal Cancer

Clinical Gastroenterology and Hepatology — Thu, 15 Oct 2009 00:00:00 +0100

Conclusions: Annual colonoscopic surveillance is recommended for individuals with HNPCC. Less intense surveillance might be appropriate for MSS families. (Source: Clinical Gastroenterology and Hepatology)

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Gynaecological cancers in genetically susceptible women: new thoughts on tubal pathology

Diagnostic Histopathology — Mon, 12 Oct 2009 00:00:00 +0100

Abstract: Women may be genetically susceptible to development of gynecological cancers. Major familial ovarian cancer syndromes include site-specific ovarian cancer, breast/ovarian cancer, and hereditary non-polyposis colon cancer (HNPCC). The former two syndromes are linked to BRCA1 and BRCA2 genes while DNA repair genes such as hMSH2 and hMLH1 are commonly involved in HNPCC. Carriers are also prone to endometrial carcinoma. BRCA mutation related ovarian tumours are more likely to be high grade serous whilst borderline tumours are conspicuously absent. Papillary serous carcinomas of the peritoneum and fallopian tube are also reported. In recent years, serous tubal intraepithelial carcinoma and transitional metaplasia, its mimick, are identified at the fimbria of prophylactic salpingo-ooph...

Aspirin Benefits People With Lynch Syndrome (HNPCC)

About.com Colon Cancer — Sun, 04 Oct 2009 23:00:00 +0100

For people with Lynch syndrome (hereditary non-polyposis colorectal cancer - HNPCC), colon cancer is an ever-present worry. The genetic condition greatly increases the chances that a person will develop this... (Source: About.com Colon Cancer)

Role of Surgery in Familial Adenomatous Polyposis and Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome)

Surgical Oncology Clinics of North America — Tue, 29 Sep 2009 17:45:32 +0100

Surgery remains the mainstay of treatment for patients who develop colorectal cancer (CRC) in the setting of a hereditary CRC syndrome. In patients with a hereditary CRC syndrome, surgery can be prophylactic, therapeutic with curative intent, and, in some cases, palliative. The type and extent of surgical resection in familial adenomatous polyposis (FAP) and in the Lynch syndrome is influenced by differences in the natural history of carcinogenesis between the two syndromes and by the effectiveness of and patient compliance with available surveillance strategies. In this article, the surgical options for the management of patients with FAP and Lynch syndrome are discussed. (Source: Surgical Oncology Clinics of North America)

The hMSH2 and hMLH1 Genes in Hereditary Nonpolyposis Colorectal Cancer

Surgical Oncology Clinics of North America — Tue, 29 Sep 2009 17:45:31 +0100

This article reviews the history of HNPCC, its clinical features, gene discovery, development of clinical genetic workup, and clinical surveillance, with an emphasis on the two major HNPCC genes, hMSH2 and hMLH1. It is not always possible to discuss these specific genes without commenting on the broader problem of HNPCC diagnosis and management. (Source: Surgical Oncology Clinics of North America)

Familial Colorectal Cancer Type X: The Other Half of Hereditary Nonpolyposis Colon Cancer Syndrome

Surgical Oncology Clinics of North America — Tue, 29 Sep 2009 17:45:31 +0100

Establishing the Amsterdam criteria, based on pedigrees, was essential for defining hereditary nonpolyposis colorectal cancer (HNPCC) syndrome in such a way that the underlying genetic cause could be identified. It is now known that about half of families that fulfill the original Amsterdam criteria have a hereditary DNA mismatch repair (MMR) gene mutation. These families may be said to have Lynch syndrome. The other half of families with HNPCC has no evidence of DNA MMR deficiency, and studies show that these families are different from families with Lynch syndrome. Familial colorectal cancer type X is the name used to refer to the “other half of HNPCC”. (Source: Surgical Oncology Clinics of North America)

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Quadruplex MAPH: improvement of throughput in high-resolution copy number screening.

BMC Genomics - Latest articles — Sun, 27 Sep 2009 23:00:00 +0100

Conclusions: QuadMAPH is an accurate, high-resolution method that allows targeted screening of large numbers of subjects without the expense of genome-wide approaches. Whilst we have applied this technique to a region of the human genome, it is equally applicable to the genomes of other organisms. (Source: BMC Genomics - Latest articles)

Cancer Risk Assessment by Rural and Appalachian Family Medicine Physicians

The Journal of Rural Health — Tue, 22 Sep 2009 23:00:00 +0100

Conclusions: Though rural Appalachian physicians do not differ in ability to identify high risk individuals, access barriers may exist for genetic testing. Interventions are needed to boost physician confidence in identifying hereditary cancer and to improve availability and awareness of availability of genetic services. (Source: The Journal of Rural Health)

Recommendations to improve identification of hereditary and familial colorectal cancer in Europe

Familial Cancer — Fri, 18 Sep 2009 06:20:01 +0100

In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment. Content Type Journal ArticleDOI 10.1007/s10689-009-9291-3Authors H. F. A. Vasen, Leiden University Medical Centre Department of Gastroenterology Leiden The NetherlandsG. Möslein, St. Josefs H...

A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations

Familial Cancer — Thu, 17 Sep 2009 12:17:26 +0100

Abstract Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome underlies between 2 and 5% of all colorectal cancer. It is inherited as an autosomal dominant condition due to mutations in the mismatch repair genes. Fifty-four non-related index cases, 21 of them fulfilling Amsterdam criteria I or II, were studied. Ten (10/21 = 47.6%) different pathological mutations were found in this group, two of which had not previously been reported—one in MLH1 and the other in MSH2-. In the remaining patients, we also found another family with one of these new mutations, and four additional changes, two of which were also new—a pathological change in MSH2 and a second change of uncertain significance in MLH1-, while the other two changes had already been rep...

Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer

Familial Cancer — Wed, 16 Sep 2009 13:01:04 +0100

Abstract The phosphatidylinositol 3-kinases-AKT-mammalian target of rapamycin pathway (PI3K/AKT/mTOR) is central in colorectal tumors. Data on its role in hereditary cancers are, however, scarce and we therefore characterized mutations in PIK3CA and KRAS, and expression of PIK3CA, phosphorylated AKT, and PTEN in colorectal cancers linked to hereditary nonpolyposis colorectal cancer (HNPCC). Sequencing was used to identify mutations in PIK3CA, a real-time PCR-based method to identify KRAS mutations, and immunohistochemical staining was used to evaluate the expression of PIK3CA, phosphorylated AKT and PTEN in 58 HNPCC-associated colorectal cancers. Derangements of at least one of the PI3K/AKT/mTOR components analyzed were found in 51/58 (88%) tumors. Mutations in PIK3CA and KR...

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A new mutation in Muir-Torre syndrome associated with familiar transmission of different gastrointestinal adenocarcinomas

European Journal of Surgical Oncology — Mon, 14 Sep 2009 16:13:11 +0100

Abstract: Hereditary Nonpolyposis Colorectal Carcinoma (HNPCC) is the most frequent inherited disease which can lead to the development of tumors in the colon and other locations. Its genetic basis is related to the germline mutation of the Mismatch Repair (MMR) genes. Muir-Torre syndrome is considered one of the subtypes of this disease, in which the HNPCC tumor spectrum is frequently associated with sebaceous carcinoma of the skin or keratoacanthoma.A 57 years old male patient is presented with a mucinous carcinoma of the caecum and an adenocarcinoma of the pancreas head. A malignant sebaceous carcinoma was removed from his left neck area. His family history was significant for two cases of colon carcinoma, two cases of stomach cancer and a case of metacron endometrial and skin tumor as...

Hnpcc

About.com Colon Cancer — Tue, 08 Sep 2009 23:00:00 +0100

Lynch syndrome, also called hereditary nonpolyposis colorectal cancer or HNPCC, is a genetic condition that increases the risk of colon and other cancers. (Source: About.com Colon Cancer)

1940's drug targets bowel cancer gene

WorldHealth.net — Fri, 04 Sep 2009 20:48:28 +0100

The drug methotrexate, first used in the 1940's, has been found to destroy the damaged MSH2 gene prevelant in people with the genetic condition HNPCC. HNPCC contributes to bowel cancer, tumors of the stomach, womb, ovaries and kidneys. MSH2 usually plays an essential role in repairing DNA damage. When the gene is damaged, mistakes in the genetic code of cells increase the risk of cancer. Methotrexate selectively destroys cells lacking the MSH2 function, providing a targeted therapy for patients with bowel cancer caused by MSH2 mutation. The research, funded by Cancer Research UK, is welcomed by independent experts. Professor Will Steward of the charity Beating Bowel Cancer says, "This is good news from one of our oldest chemotherapy drugs. It won't be for everyone, but it does hold out hop...

Molecular Analysis of Endometrial Tumorigenesis: Importance of Complex Hyperplasia Regardless of Atypia.

Clinical Cancer Research — Mon, 31 Aug 2009 23:00:00 +0100

CONCLUSIONS: Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma. (Clin Cancer Res 2009;15(18):OF1-12). PMID: 19723644 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Comprehensive Molecular Analysis of Mismatch Repair Gene Defects in Suspected Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Cases

Cancer Research — Sun, 30 Aug 2009 23:00:00 +0100

An accurate algorithm is essential for effective molecular diagnosis of hereditary colorectal cancer (CRC). Here, we have extended the analysis of 71 CRC cases suspected to be Lynch syndrome cases for MSH2, MLH1, MSH6, and PMS2 gene defects. All cases were screened for mutations in MSH2, MLH1, and MSH6, and all cases where tumors were available were screened for microsatellite instability (MSI) and expression of MSH2 and MLH1. Subsequently, mutation-negative cases were screened for MLH1 methylation and mutations in PMS2. Of the MSI-high (MSI-H) cases, 96% had a mismatch repair (MMR) gene defect, mostly involving MSH2 or MLH1; one PMS2 mutation, one MLH1 epimutation, and no MSH6 mutations were found. Four of the 28 MSI-H cases, including one Amsterdam criteria case, had biallelic tumor MLH1...

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60-Year-Old Drug Shows New Promise For Inherited Cancer

Health News from Medical News Today — Fri, 28 Aug 2009 07:00:00 +0100

Cancer Research UK-funded scientists have shown that an early chemotherapy drug invented in the 1940s has the potential to work against a genetic fault called HNPCC* which is linked to bowel and other cancers. The results are published in EMBO Molecular Medicine** today, (Thursday). HNPCC is a hereditary condition involved in around five per cent of all bowel cancer cases. (Source: Health News from Medical News Today)

Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2

EMBO Molecular Medicine — Thu, 27 Aug 2009 23:00:00 +0100

Mutations in the MSH2 gene predispose to a number of tumourigenic conditions, including hereditary non-polyposis colon cancer (HNPCC). MSH2 encodes a protein in the mismatch repair (MMR) pathway which is involved in the removal of mispairs originating during replication or from damaged DNA. To identify new therapeutic strategies for the treatment of cancer arising from MMR deficiency, we screened a small molecule library encompassing previously utilized drugs and drug-like molecules to identify agents selectively lethal to cells lacking functional MSH2. This approach identified the drug methotrexate as being highly selective for cells with MSH2 deficiency. Methotrexate treatment caused the accumulation of potentially lethal 8-hydroxy-2'-deoxyguanosine (8-OHdG) oxidative DNA lesions in both...

Nonfluorescent Denaturing HPLC-Based Primer-Extension Method for Allele-Specific Expression: Application to Analysis of Mismatch Repair Genes [Molecular Diagnostics and Genetics]

Clinical Chemistry — Thu, 27 Aug 2009 23:00:00 +0100

Conclusions: Independent DHPLC-based primer-extension assays for measuring and confirming ASE can be developed for different sequence variants of interest. This DHPLC application provides a cost-effective method for detecting ASE in cases for which conventional screening fails to detect pathogenic mutations in candidate genes and may be applicable for confirming ASE revealed by other methods, such as those used for transcriptome-wide analyses. . (Source: Clinical Chemistry)

Colorectal cancer in Iran: immunohistochemical profiles of four mismatch repair proteins

International Journal of Colorectal Disease — Tue, 25 Aug 2009 16:45:47 +0100

Conclusions Along with the recommendations of the National Institute of Cancer, we recommend immunohistochemistry staining for MLH1, MSH2, PMS2, and MSH6 for determining the eligibility of patients for mutation analysis of MMR genes. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00384-009-0784-1Authors Mahsa Molaei, Shahid Beheshti University M.C. Department of Pathology, Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital Tehran IranBabak Khoshkrood Mansoori, Shahid Beheshti University M.C. Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital Tehran IranSomayeh Ghiasi, Shahid Beheshti University M.C. Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital Tehran IranFatemeh ...

Functional characterization of rare missense mutations in MLH1 and MSH2 identified in Danish colorectal cancer patients

Familial Cancer — Thu, 20 Aug 2009 19:58:19 +0100

In conclusion, only 1/10 missense mutations displayed repair deficiency and could be classified as pathogenic. No final conclusion can be drawn on the MSH2 p.Met688Val mutation, which caused reduced protein expression. Although, no deficiencies have been identified in the proteins harbouring the other missense mutations, pathogenicity of these variants cannot be unambiguously excluded. Content Type Journal ArticleDOI 10.1007/s10689-009-9274-4Authors Lise Lotte Christensen, Aarhus University Hospital Molecular Diagnostic Laboratory Skejby DenmarkReetta Kariola, University of Helsinki Department of Biological and Environmental Sciences, Genetics Helsinki FinlandMari K. Korhonen, University of Helsinki Department of Biological and Environmental Sciences, Genetics Helsinki FinlandFried...

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Cancer risk in a cohort of subjects carrying a single mismatch repair gene mutation

Familial Cancer — Mon, 17 Aug 2009 19:02:07 +0100

Abstract Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant condition, caused by germline mutations in the mismatch repair genes, that presents with colorectal cancers at a young age, as well as extracolonic tumours. One of the causative mutations is the C1528T (Exon 13) mutation of the MLH1 gene. The purpose of this study is to document the cancer risk for subjects who carry this mutation. This is a prospective cohort study of 200 subjects who carry this mutation. We calculated the risk of developing colorectal cancer only in those subjects who had not undergone surveillance colonoscopy. The incidence of extracolonic cancers (for which surveillance is not routinely offered) was determined for the entire cohort. The results of the study are among the 71...

Determination of splice-site mutations in Lynch syndrome (hereditary non-polyposis colorectal cancer) patients using functional splicing assay

Familial Cancer — Sat, 15 Aug 2009 09:58:39 +0100

Abstract Lynch syndrome (hereditary non-polyposis colorectal cancer) is an inherited disease caused by germ-line mutation in mismatch repair genes such as MLH1, MSH2, and MSH6. The mutations include missense and nonsense mutations, small insertions and deletions, and gross genetic alterations including large deletions and duplications. In addition to these genetic changes, mutations in introns are also involved in the pathogenesis. However, it is sometimes difficult to interpret correctly the pathogenicity of variants in exons as well as introns. To evaluate the effect of splice-site mutations in two Lynch syndrome patients, we carried out a functional splicing assay using minigenes. Consequently, this assay showed that the mutation of c.1731+5G>A in MLH1 led to exon15 s...

Absence of germline mono-allelic promoter hypermethylation of the CDH1 gene in gastric cancer patients

Molecular Cancer — Tue, 11 Aug 2009 23:00:00 +0100

Conclusions: These results suggest that germline mono-allelic hypermethylation of the CDH1 promoter is not a major predisposing factor for gastric cancer. (Source: Molecular Cancer)

Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing

Familial Cancer — Sun, 09 Aug 2009 07:20:45 +0100

Abstract Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is one of the commonest cancer susceptibility syndromes. It is characterized by early onset colon cancer and a variety of extracolonic tumours. Germline mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for this disorder. Identifying an affected individual depends on the tumour histopathology, family history that fulfils the Amsterdam and/or Bethesda criteria, tumour immunohistochemistry, microsatellite instability, and finally molecular analysis of an affected member. It is a laborious, time consuming and expensive procedure, which needs the effort of a multi-disciplinary team. However, once the diagnosis is established and germline defect is identified...

A MLH1 polymorphism that increases cancer risk is associated with better outcome in sporadic colorectal cancer

Cancer Genetics and Cytogenetics — Sat, 08 Aug 2009 11:53:07 +0100

Abstract: Germline mutations or the malfunctioning of postreplicative mismatch repair genes (MMR) are responsible of hereditary nonpolyposis colorectal cancer (HNPCC), and are also implied in some sporadic colorectal cancer (CRC) forms without any familial history of this disease. Besides germinal mutations and methylation, single-nucleotide polymorphisms (SNP) can predispose to nonfamilial CRC with low to moderate penetrance. In this case–control study, we analyzed three MLH1 single-nucleotide polymorphisms (exon 5: 415G→C, rs28930073; exon 8: 655A→G, rs1799977 and exon 16: 1852-1853AA→GC) in 140 sporadic colorectal cancer cases and 125 healthy individuals to evaluate the relationship among CRC risk and clinicopathologic and genetic characteristics of the tumors. In our study, no ...

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[Reviews] Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma

Journal of Clinical Pathology — Mon, 27 Jul 2009 23:00:00 +0100

Women with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome have a high risk for endometrial cancer (EC) and frequently present with a gynaecological cancer as their first or sentinel malignancy. Identification of these patients is important given their personal and family risk for synchronous and metachronous tumours. Modalities to detect ECs for the possibility of HNPCC include microsatellite instability assay, immunohistochemistry for DNA mismatch repair proteins, MLH1 promoter hypermethylation assay and mutational analysis of DNA mismatch repair genes. The revised Bethesda guidelines provide screening criteria for HNPCC in colorectal cancers (CRCs). However, there are currently no such screening recommendations for women with endometrial carcinoma. While age and family...

Lynch Syndrome(HNPCC) - Know the Risks

About.com Colon Cancer — Sun, 26 Jul 2009 23:00:00 +0100

Lynch syndrome, or Hereditary Nonpolyposis Colorectal Cancer (HNPCC), greatly increases risk of colon cancer in people who have this condition. Health experts believe that Lynch syndrome, which is due to... (Source: About.com Colon Cancer)

Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome

Breast Cancer Research and Treatment — Mon, 06 Jul 2009 16:17:33 +0100

Abstract Whether or not breast cancer can be a feature of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has been debated. In order to clarify if defective mismatch repair (MMR) may indeed play a role in breast cancer, we used the Danish HNPCC register to identify all breast cancers that occurred in MMR gene mutation carriers. In total, 20 female mutation carriers were diagnosed with breast cancer at mean 50 years of age. These tumors were predominantly ductal carcinomas with extensive lymphocytic reactions in 8/14 evaluated tumors. MMR protein immunostaining showed loss of expression of MLH1, MSH2 or MSH6 corresponding to the mutations identified in 7 of the 16 cases investigated, and these tumors were diagnosed at mean 50 (33–66) years of age. ...

Somatic mutations of the CDC4 (FBXW7) gene in hereditary colorectal tumors.

Oncology — Sat, 27 Jun 2009 13:42:03 +0100

CONCLUSIONS: The results indicate that the frequency of CDC4 mutations in colorectal tumors is similar in patients with HNPCC and FAP compared to patients with sporadic carcinomas. Moreover, infrequent LOH suggests that the CDC4 gene does not follow the general 2-hit model. PMID: 19420964 [PubMed - indexed for MEDLINE] (Source: Oncology)