MedWorm: HNPCC

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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[Lynch syndrome - epidemiology, clinical features, molecular genetics, screening, therapy].

Zeitschrift fur Gastroenterologie — Wed, 01 Feb 2012 05:00:00 +0100

Authors: Schneider R, Fürst A, Möslein G Abstract Lynch syndrome is characterised by a familial predisposition of colorectal and endometrial carcinomas in association with a variety of other cancers. The underlying autosomal dominant inheritance has a penetrance of 85 - 90 %. The molecular genetic underlying mechanism is a mutation in one of the mismatch-repair genes. The identification of the molecular genetic basis of Lynch syndrome enabled the implementation of predictive testing in families with a proven mutation. A prerequisite to detect patients with Lynch syndrome is a knowledge of the clinical and histopathological features of this disease. Typical for Lynch syndrome associated carcinomas is the early age of onset of about 45 years as well as the characteristic localisa...

Classification of mismatch repair gene missense variants with PON‐MMR

Human Mutation — Mon, 30 Jan 2012 05:00:00 +0100

AbstractNumerous mismatch repair (MMR) gene variants have been identified in Lynch syndrome and other cancer patients, but knowledge about their pathogenicity is frequently missing. The diagnosis and treatment of patients would benefit from knowing which variants are disease‐related. Bioinformatic approaches are well suited to the problem and can handle large numbers of cases. Functional effects were revealed based on literature for 168 MMR missense variants. Performance of numerous prediction methods was tested with this dataset. Among the tested tools only the results of tolerance prediction methods correlated to functional information, however with poor performance. Therefore a novel consensus based predictor was developed. The novel prediction method, PON‐MMR, achieved accuracy of ...

Tumor spectrum in lynch syndrome, DNA mismatch repair system and endogenous carcinogens

Journal of Surgical Oncology — Thu, 26 Jan 2012 13:16:10 +0100

AbstractInactivation of Mismatch Repair genes in Lynch Syndrome, caused by inherited mutations, decreases the ability to repair DNA errors throughout life. This deficit may allow the development of any tumor type. Nevertheless, the Syndrome develops a specific tumor spectrum associated with the disease. We think that such spectrum of tumors would be related to the action of certain endogenous carcinogens such as bile acids and estrogens that aggravate the inherited defect. J. Surg. Oncol © 2012 Wiley Periodicals, Inc. (Source: Journal of Surgical Oncology)

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

European Journal of Human Genetics — Wed, 25 Jan 2012 05:00:00 +0100

Authors: Mireia Gausachs, Pilar Mur, Julieta Corral, Marta Pineda, Sara González, Llúcia Benito, Mireia Menéndez, Josep Alfons Espinàs, Joan Brunet, María Dolores Iniesta, Stephen B Gruber, Conxi Lázaro, Ignacio Blanco & Gabriel Capellá (Source: European Journal of Human Genetics)

Infiltration of Lynch colorectal cancers by activated immune cells associates with early staging of the primary tumor and absence of lymph node metastases.

Clinical Cancer Research — Wed, 18 Jan 2012 05:00:00 +0100

CONCLUSIONS: The immune system assumes an important role in counteracting the progression of Lynch colorectal cancers and in selecting abnormal HLA class I phenotypes. Our findings support the development of clinical strategies that explore the host's natural anti-tumor immune responses. PMID: 22261803 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

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Genetic Risk and Gynecologic Cancers

Hematology/Oncology Clinics of North America — Tue, 17 Jan 2012 12:47:50 +0100

Hereditary cancer syndromes are responsible for 5% of endometrial cancers and 10% of ovarian cancers. Hereditary breast and ovarian cancer syndrome and Lynch syndrome account for most of these inherited cases. Significant advances have been made in the identification and management of women with these syndromes. In addition, recent advances have highlighted the prognostic and therapeutic implications for women with gynecologic cancers and inherited cancer syndromes. (Source: Hematology/Oncology Clinics of North America)

Can a gastrointestinal pathologist identify microsatellite instability in colorectal cancer with reproducibility and a high degree of specificity?

Familial Cancer — Fri, 13 Jan 2012 16:56:24 +0100

Conclusions; PathScore identified the most proven MSI-H CRCs at lowest cost and even an experienced gastrointestinal pathologist has difficulties identify MSI-H without scoring. So, scoring can be facilitated by a computerized evaluation form for routine CRC histology, prompting score computation and recommendation for MSI analysis with high specificity. Content Type Journal ArticleCategory Original ArticlePages 1-9DOI 10.1007/s10689-012-9508-8Authors Eli Brazowski, Department of Pathology, Tel Aviv Medical Center, 6 Weizmann Street, 64239 Tel Aviv, IsraelPaul Rozen, Department of Gastroenterology, Tel Aviv Medical Center, 6 Weizmann Street, 64239 Tel Aviv, IsraelSara Pel, Department of Gastroenterology, Tel Aviv Medical Center, 6 Weizmann Street, 64239 Tel Aviv, IsraelZiona Samue...

LINE-1 hypomethylation in familial and sporadic cancer

Journal of Molecular Medicine — Sat, 07 Jan 2012 16:55:24 +0100

Abstract Increased and decreased methylation at specific sequences (hypermethylation and hypomethylation, respectively) is characteristic of tumor DNA compared to normal DNA and promotes carcinogenesis in multiple ways including genomic instability. Long interspersed element (LINE), an abundant class of retrotransposons, provides a surrogate marker for global hypomethylation. We developed methylation-specific multiplex ligation-dependent probe amplification assays to study LINE-1 methylation in cases of colorectal, gastric, and endometrial cancer (N = 276), stratified by patient category [sporadic; Lynch syndrome (LS); familial colorectal cancer type X (FCCX)] and microsatellite instability status. Within each patient group, LINE-1 showed lower methylation in tumor DNA ...

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)

Optimal Treatment Strategies for Localized and Advanced Microsatellite Instability–High Colorectal Cancer

Current Colorectal Cancer Reports — Fri, 06 Jan 2012 16:45:08 +0100

Abstract The defective mismatch repair phenotype (MMR-D) has been recognized as a distinct form of colorectal cancers with specific clinical and biologic features. It is caused by a lack of expression of mismatch repair enzymes in tumor cells either on the basis of hereditary or sporadic mutation of gene(s) encoding the enzymes such as in the Lynch syndrome, or by silencing of gene transcription due to promoter methylation. Colorectal cancers of the MMR-D phenotype have consistently shown to be associated with good prognosis and are likely, at least in early-stage disease, resistant to fluoropyrimidine monotherapy. These characteristics have significant implications for clinical practice and treatment strategies, particularly in the adjuvant setting. Content Type Journ...

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Cervical Adenocarcinoma in a Patient With Lynch Syndrome, Muir-Torre Variant [DIAGNOSIS IN ONCOLOGY]

Journal of Clinical Oncology — Fri, 06 Jan 2012 05:00:00 +0100

(Source: Journal of Clinical Oncology)

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...

Altered methylation at microRNA-associated CpG islands in hereditary and sporadic carcinomas: a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA)-based approach.

Molecular Medicine — Thu, 29 Dec 2011 07:24:03 +0100

Authors: Pavicic W, Perkiö E, Kaur S, Peltomäki P Abstract MicroRNAs (miRNAs) are small noncoding RNAs that contribute to tumorigenesis by acting as oncogenes or tumor suppressor genes and may be important in the diagnosis, prognosis and treatment of cancer. Many miRNA genes have associated CpG islands, suggesting epigenetic regulation of their expression. Compared with sporadic cancers, the role of miRNAs in hereditary or familial cancer is poorly understood. We investigated 96 colorectal carcinomas, 58 gastric carcinomas and 41 endometrial carcinomas, occurring as part of inherited DNA mismatch repair (MMR) deficiency (Lynch syndrome), familial colorectal carcinoma without MMR gene mutations or sporadically. Methylation-specific multiplex ligation-dependent probe amplification ...

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...

Microsatellite Instability in Saliva from Patients with Hereditary Non-polyposis Colon Cancer and Siblings Carrying Germline Mismatch Repair Gene Mutations.

Annals of Clinical and Laboratory Science — Fri, 23 Dec 2011 21:54:02 +0100

Authors: Hu P, Lee CW, Xu JP, Simien C, Fan CL, Tam M, Ramagli L, Brown BW, Lynch P, Frazier ML, Siciliano MJ, Coolbaugh-Murphy M Abstract Microsatellites are short tandem repeats of deoxyribonucleic acid (DNA) sequences which are distributed throughout the genome. Tumors in patients with Lynch syndrome tend to accumulate mutations in microsatellites at a much higher rate than other sequences in the genome resulting in microsatellite instability (MSI). This is due to germline mutations in mismatch repair (MMR) genes. Using small pool-polymerase chain reaction (SP-PCR), previous studies have shown that mutant alleles can be detected in microsatellites of DNA from peripheral blood lymphocytes (PBLs) of Lynch syndrome patients at frequencies that were low, but significantly higher tha...

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Systematic Immunohistochemistry Screening for Lynch Syndrome in Early Age-of-Onset Colorectal Cancer Patients Undergoing Surgical Resection

Journal of the American College of Surgeons — Fri, 23 Dec 2011 00:08:09 +0100

Conclusions: Reflex IHC testing for LS on early age-of-onset CRC patients undergoing resection is feasible at the institutional level. This strategy identifies a substantial number of LS patients who would have been missed if genetic testing was based on the Amsterdam II Criteria alone. (Source: Journal of the American College of Surgeons)

Pathogenicity of A600V Variant in Exon 12 of the MSH2 Gene Detected in a Japanese Kindred with Lynch Syndrome

Japanese Journal of Clinical Oncology — Thu, 22 Dec 2011 05:00:00 +0100

In this report, we confirm the same mutation in his 66-year-old mother who had cecal cancer. PCR/direct sequencing analysis of peripheral blood lymphocytes revealed the same missense mutation in exon 12 at codon 600 of the MSH2 gene. The wave height of the capillary sequencer from the wild-type allele was decreased in tumor tissue, indicating loss of heterozygosity in the wild-type allele. Analysis of the tumor showed microsatellite instability high and loss of MSH2 protein expression. This sequence variant has not been reported in another family. This mutation is considered to play a significant and causative role in Lynch syndrome. (Source: Japanese Journal of Clinical Oncology)

Screening to detect Lynch syndrome and prevent hereditary cancers in relatives

Journal of Medical Screening — Mon, 19 Dec 2011 05:00:00 +0100

(Source: Journal of Medical Screening)

Covering the Cover

Gastroenterology — Mon, 19 Dec 2011 05:00:00 +0100

Tobacco remains the most preventable cause of death in the world. Evidence supporting a carcinogenic role for tobacco has now expanded to 18 cancers. In this issue of Gastroenterology, 2 studies provide evidence that tobacco use, mainly in the form of cigarette smoking, increases the risk of colorectal adenoma formation in patients with the Lynch syndrome, and the development of high-grade dysplasia and cancer among patients with Barrett's esophagus. The 2 studies indicate that lifestyle changes such as abstention from tobacco use can affect predisposed individuals. (Source: Gastroenterology)

Molecular typing of colorectal cancer: applications in diagnosis and treatment

Diagnostic Histopathology — Mon, 19 Dec 2011 05:00:00 +0100

Abstract: Molecular typing of colorectal cancer (CRC) is at an early stage of development with analysis of KRAS mutation status and DNA mismatch repair (MMR) deficiency representing the two major approaches currently in use for diagnosis and treatment-related purposes. RAS proteins act as molecular switches that regulate cellular processes including cell growth and survival. Activating KRAS mutations are found in 40–50% of colorectal adenomas and cancers. Detection of KRAS mutations guide the decision to use anti-EGFR antibody therapy, which is not effective in KRAS mutant cancers. MMR deficiency results in failure to repair replication-associated DNA errors, allowing persistence of mismatch mutations all over the genome, especially in regions of repetitive DNA known as microsatellites, ...

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[Comment] Aspirin and colorectal cancer prevention in Lynch syndrome

LANCET — Fri, 16 Dec 2011 12:02:44 +0100

More than 600 000 people worldwide die of colorectal cancer annually, making development of effective preventive agents for this disease a high priority. One of the most promising such agents, aspirin, is the subject of a major report in The Lancet by John Burn and colleagues. In previous work, four placebo-controlled randomised trials showed that aspirin reduced risk of colorectal adenomas, precursor of almost all colorectal cancers, in patients with a history of adenoma or colorectal cancer. A randomised trial in familial adenomatous polyposis suggested that aspirin may protect against adenoma development. (Source: LANCET)

[Articles] Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

LANCET — Fri, 16 Dec 2011 12:02:44 +0100

SummaryBackgroundObservational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. (Source: LANCET)

Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow‐up of a kindred

Pediatric Blood and Cancer — Fri, 16 Dec 2011 05:00:00 +0100

ConclusionsWe report on the long‐term outcome in patients with biallelic MMR mutations who benefited from prophylactic cancer surveillance. Genetic screening and subsequent surveillance led to earlier recognition of asymptomatic tumors at stages more amenable to resection and probable cure. Multicenter collaboration and implementation of surveillance guidelines is necessary to further determine genotype–phenotype correlations. Pediatr Blood Cancer © 2011 Wiley Periodicals, Inc. (Source: Pediatric Blood and Cancer)

Cancer Risk Elevated in Myotonic Muscular DystrophyCancer Risk Elevated in Myotonic Muscular Dystrophy

Medscape Today Headlines — Thu, 15 Dec 2011 19:55:21 +0100

Swedish and Danish registry data provide strong epidemiologic evidence that MMD may be a cancer susceptibility disorder, similar to Lynch syndrome, researchers say. Medscape Medical News (Source: Medscape Today Headlines)

8q23.3 and 11q23.1 as modifying loci influencing the risk for CRC in Lynch syndrome

European Journal of Human Genetics — Wed, 14 Dec 2011 05:00:00 +0100

Authors: Bente A Talseth-Palmer, Rodney J Scott, Hans F A Vasen & Juul T Wijnen (Source: European Journal of Human Genetics)

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DXMS Revealed ATP-dependent Structural Change of MutL [Molecular Bases of Disease]

Journal of Biological Chemistry — Fri, 02 Dec 2011 05:00:00 +0100

In this study, we investigated the effect of ATP binding on the structure of MutL. First, a cross-linking experiment confirmed that the N-terminal ATPase domain physically interacts with the C-terminal endonuclease domain. Next, hydrogen/deuterium exchange mass spectrometry clarified that the binding of ATP to the N-terminal domain induces local structural changes at the catalytic sites of MutL C-terminal domain. Finally, on the basis of the results of the hydrogen/deuterium exchange experiment, we successfully identified novel regions essential for the endonuclease activity of MutL. The results clearly show that ATP modulates the nicking endonuclease activity of MutL via structural rearrangements of the catalytic site. In addition, several Lynch syndrome-related mutations in human MutL ho...

{beta}-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness [Biochemistry]

Proceedings of the National Academy of Sciences — Tue, 29 Nov 2011 05:00:00 +0100

In most carcinomas, invasion of malignant cells into surrounding tissues involves their molecular reprogramming as part of an epithelial-to-mesenchymal transition (EMT). Mutation of the APC gene in most colorectal carcinomas (CRCs) contributes to the nuclear translocation of the oncoprotein β-catenin that upon binding to T-cell and lymphoid enhancer (TCF-LEF) factors triggers an EMT and a proinvasive gene expression profile. A key inducer of EMT is the ZEB1 transcription factor whose expression promotes tumorigenesis and metastasis in carcinomas. As inhibitor of the epithelial phenotype, ZEB1 is never present in the epithelium of normal colon or the tumor center of CRCs where β-catenin remains membranous. We show here that ZEB1 is expressed by epithelial cells in intestinal tumors from h...

A state-wide population-based program for detection of lynch syndrome based upon immunohistochemical and molecular testing of colorectal tumours

Familial Cancer — Fri, 25 Nov 2011 17:57:23 +0100

Abstract We have previously established in a large retrospective study that testing for microsatellite instability (MSI) in colorectal cancer (CRC) from patients aged <60 years was an effective first screen to identify individuals with Lynch syndrome (LS). From these findings, MSI and/or immunohistochemical (IHC) screening was recommended for all newly diagnosed CRC patients aged <60 years in Western Australia, regardless of family history of cancer. In the current study we evaluated the utility of routine MSI/IHC screening by diagnostic pathology laboratories for the detection of previously undiagnosed individuals and families with LS. From January 2009 to December 2010, 270 tumours were tested for MSI and for expression of MLH1, PMS2, MSH2 and MSH6 using ...

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...

Yield of routine molecular analyses in colorectal cancer patients ≤ 70 years to detect underlying Lynch syndrome

The Journal of Pathology — Thu, 17 Nov 2011 08:25:57 +0100

In conclusion, molecular screening for LS in CRC patients ≤ 70 years leads to identification of a molecular profile compatible with LS in 4.5% of patients, with most of them not fulfilling the age‐criterion (≤ 50 years) routinely used for LS‐assessment. Routine use of MSI‐testing may be considered in CRC patients up to the age of 70 years, with a central role for the pathologist in the selection of patients. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology)

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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...

Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome

The Journal of Pathology — Mon, 14 Nov 2011 05:00:00 +0100

In conclusion, molecular screening for LS in CRC patients ≤70 years leads to identification of a molecular profile compatible with LS in 4.5% of patients, with most of them not fulfilling the age criterion (≤50 years) routinely used for LS assessment. Routine use of MSI testing may be considered in CRC patients up to the age of 70 years, with a central role for the pathologist in the selection of patients. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology)

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)

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Smoking Increases the Risk for Colorectal Adenomas in Patients With Lynch Syndrome

Gastroenterology — Mon, 07 Nov 2011 05:00:00 +0100

Conclusions: Among people with Lynch syndrome, current smokers have an increased risk of colorectal adenomas. Former smokers have a lower risk than current smokers, but greater risk than never smokers. Individuals with Lynch syndrome should be encouraged to avoid smoking. (Source: Gastroenterology)

Inherited colorectal cancer syndromes.

Cancer Journal — Tue, 01 Nov 2011 04:00:00 +0100

Authors: Kastrinos F, Syngal S Abstract ABSTRACT: Colorectal cancer is the most common gastrointestinal malignancy and the second leading cause of cancer death in both men and women in the United States. Most colorectal cancer cases diagnosed annually are due to sporadic events, but up to 5% are attributed to known monogenic disorders including Lynch syndrome, familial adenomatous polyposis, MYH-associated polyposis, and the rare hamartomatous polyposis syndromes. These inherited colorectal cancer syndromes confer a markedly increased risk for the development of multiple cancers, and predictive genetic testing is available to identify mutation carriers and at-risk family members. Through personalized strategies for diagnosis and management, a substantial reduction in morbidity and ...

Daily Aspirin May Help Prevent Colon Cancer for Those at High Risk

The Doctors Lounge - Oncology — Sun, 30 Oct 2011 04:00:00 +0100

People with Lynch syndrome, a hereditary form of cancer, might benefit from 2 tablets a day: study (Source: The Doctors Lounge - Oncology)

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...

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Aspirin 'reduces cancer rates'

Telegraph Health — Fri, 28 Oct 2011 10:49:25 +0100

Regular doses of aspirn can cut bowel cancer rates by nearly two thirds in people suffering with Lynch Syndrome, a study has found. (Source: Telegraph Health)

Aspirin associated with colorectal cancer prevention in Lynch syndrome

HemOncToday.com — Fri, 28 Oct 2011 09:58:00 +0100

(Source: HemOncToday.com)

Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: analysis from CAPP2 study

NeLM - News — Fri, 28 Oct 2011 04:00:00 +0100

Source: Lancet Area: News Over 600,000 people worldwide die of colorectal cancer annually, thus the need for effective preventive agents is a high priority. One promising agent is aspirin, which has been shown in four placebo-controlled randomised trials to reduce the risk of colorectal adenomas, precursor of almost all colorectal cancers, in patients with a history of adenoma or colorectal cancer. A trial in familial adenomatous polyposis suggested that aspirin may protect against adenoma development. A meta-analysis of long-term data from five randomised trials of cardiovascular prevention noted that aspirin was associated with a 24% reduction in the 20-year risk of colorectal cancer and 35% reduction in associated mortality. However, a definitive conclusion can only be drawn from a ran...

Aspirin Chemoprevention Now Recommended in Lynch SyndromeAspirin Chemoprevention Now Recommended in Lynch Syndrome

Medscape Today Headlines — Thu, 27 Oct 2011 23:01:00 +0100

Results from a decade-long trial show that aspirin taken regularly halved the risk of developing cancer in individuals with this hereditary disorder. Medscape Medical News (Source: Medscape Today Headlines)

Daily Aspirin May Help Prevent Colon Cancer for Those at High Risk

MedlinePlus Health News — Thu, 27 Oct 2011 23:00:00 +0100

People with Lynch syndrome, a hereditary form of cancer, might benefit from 2 tablets a day: study Source: HealthDay Related MedlinePlus Pages: Colorectal Cancer, Pain Relievers (Source: MedlinePlus Health News)

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Evidence for breast cancer as an integral part of lynch syndrome

Genes, Chromosomes and Cancer — Thu, 27 Oct 2011 04:00:00 +0100

This study aimed at clarifying the heavily debated issue of breast cancer being part of Lynch syndrome. Detailed clinical data on cancer occurrence in Swiss female MLH1/MSH2 mutation carriers were gathered, all available breast cancer specimens assessed for molecular evidence for MMR deficiency (i.e., microsatellite instability (MSI), MMR protein expression, and somatic (epi)genetic MMR gene alterations) and compiled with the scarce molecular data available from the literature. Seventy unrelated Swiss Lynch syndrome families were investigated comprising 632 female family members at risk of which 92 were genetically verified mutation carriers (52 MLH1 and 40 MSH2). On contrast to endometrial and ovarian cancer, which occurred significantly more often and at younger age in MLH1/MSH2 mutation...

Feasibility of laparoscopic restorative proctocolectomy without diverting stoma

Digestive and Liver Disease — Mon, 24 Oct 2011 04:00:00 +0100

Conclusion: Laparoscopic restorative proctocolectomy can be performed safely without a diverting stoma in selected patients. (Source: Digestive and Liver Disease)

Detection of DNA mismatch repair proteins in fresh human blood lymphocytes - towards a novel method for Hereditary Non-Polyposis Colorectal Cancer (Lynch Syndrome) screening

Journal of Experimental and Clinical Cancer Research — Fri, 21 Oct 2011 04:00:00 +0100

Conclusions: Finding that MMR protein levels can be measured in fresh lymphocytes, and given that cells with heterozygote MMR mutations have reduced levels of full-length MMR proteins, suggests that our immunoassay could be advanced to a quantitative test for screening populations at high risk for LS. (Source: Journal of Experimental and Clinical Cancer Research)

Impact of Colonoscopic Screening in Male and Female Lynch Syndrome Carriers with an MSH2 Mutation.

Clinical Genetics — Wed, 19 Oct 2011 04:00:00 +0100

Conclusions: Although colonoscopic screening was associated with decreased CRC risk and better survival, CRCs continued to occur. CRC development may be further reduced by decreasing the screening interval to one year and improving quality of colonoscopy. PMID: 22011075 [PubMed - as supplied by publisher] (Source: Clinical Genetics)

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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Endometrial Carcinomas: A Review Emphasizing Overlapping and Distinctive Morphological and Immunohistochemical Features

Advances in Anatomic Pathology — Sat, 15 Oct 2011 19:38:22 +0100

This review focuses on the most common diagnostic pitfalls and helpful morphologic and immunohistochemical markers in the differential diagnosis between the different subtypes of endometrial carcinomas, including: (1) endometrioid versus serous glandular carcinoma, (2) papillary endometrioid (not otherwise specified, villoglandular and nonvillous variants) versus serous carcinoma, (3) endometrioid carcinoma with spindle cells, hyalinization, and heterologous components versus malignant mixed müllerian tumor, (4) high-grade endometrioid versus serous carcinoma, (5) high-grade endometrioid carcinoma versus dedifferentiated or undifferentiated carcinoma, (6) endometrioid carcinoma with clear cells versus clear cell carcinoma, (7) clear cell versus serous carcinoma, (8) undifferentiated versu...

Microsatellite instability and colorectal cancer.

Archives of Pathology and Laboratory Medicine — Sat, 01 Oct 2011 04:00:00 +0100

Conclusions.-Universal screening for Lynch syndrome in all individuals affected with colorectal cancer has been recommended by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Preliminary screening tests can identify individuals unlikely to be affected by Lynch syndrome, thereby reducing the need for full gene analysis. Immunohistochemistry and polymerase chain reaction-based tests for microsatellite instability have similar clinical sensitivity and specificity, and each method has advantages and limitations. BRAF and MLH1 methylation testing are useful reflex tests for those with a defect in MLH1 identified by immunohistochemistry. Emerging technologies, such as high-throughput sequencing, may substantially affect diagnostic algorithms in the future. PM...

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)

Endometrial cancer patients and compliance with genetic counseling: Room for improvement.

Gynecologic Oncology — Sat, 01 Oct 2011 04:00:00 +0100

CONCLUSION: Most patients underestimate their risk of LS associated heritable cancer. Physicians should pay more attention to family history and IHC in order to refer patients appropriately. In addition, more verbal and written information may enable patients to accurately assess their cancer risk. This could further improve compliance with genetic counseling and detection of Lynch syndrome. PMID: 21968342 [PubMed - as supplied by publisher] (Source: Gynecologic Oncology)

Colorectal cancer family history assessment.

Clinical Journal of Oncology Nursing — Sat, 01 Oct 2011 00:25:23 +0100

This article describes family history assessment for colorectal cancer in three outpatient gastroenterology units and examines gastroenterology unit nurses' knowledge and attitudes about family history assessments. Eighty-eight colonoscopy records were surveyed, and 16 RNs were interviewed. The medical record documentation was surveyed using a researcher-developed tool to identify type of cancer, age at disease onset, family relationship, and number of family members with cancer. Gastroenterology unit nurses were interviewed to assess knowledge and attitudes about family history assessment regarding colorectal cancer. Findings indicate that limited family history documentation was present in the medical record and that important age-at-disease-onset information was missing in 95% of patien...

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Influence of Eight Unclassified Missense Variants of the MLH1 Gene on Lynch Syndrome Susceptibility.

Biochemical Genetics — Wed, 28 Sep 2011 04:00:00 +0100

In this study, we attempt to evaluate the etiological role of eight MLH1 missense variants. The variants were analyzed for their ability to affect MLH1 protein interaction with its partner PMS2 in vivo employing a yeast two-hybrid system. In addition, a SIFT (sorting intolerant from tolerant) algorithm was adopted to predict the effects of amino acid substitutions. Finally, scanning of mutations in a normal Chinese population and assay of the clinical characteristics have all been taken into account. Our results demonstrated that the MLH1 variants D485E and L653R cause functional alterations of the human MutLα complex significantly. The R265C, D304V, A586P, and R755S variants affect partial interaction. The remaining two variants, N38D and L559R, could be nonfunctional polymorphisms or mi...

[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)

Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility

Human Mutation — Fri, 23 Sep 2011 03:39:23 +0100

In this study, we evaluated the contribution of constitutional epimutations of MMR genes in Lynch syndrome. A cohort of 134 unrelated Lynch syndrome‐suspected patients without MMR germline mutation was screened for constitutional epimutations of MLH1 and MSH2 by quantitative bisulfite pyrosequencing. Patients were also screened for the presence of EPCAM deletions, a possible cause of MSH2 methylation. Tumors from patients with constitutional epimutations were extensively analyzed. We identified a constitutional MLH1 epimutation in two proband patients. For one of them, we report for the first time evidence of transmission to two children who also developed early colonic tumors, indicating that constitutional MLH1 epimutations are associated to a real risk of transgenerational inheritance...

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...

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Novel lovd databases for hereditary breast cancer and colorectal cancer genes in the chinese population

Human Mutation — Wed, 07 Sep 2011 04:00:00 +0100

AbstractThe Human Variome Project (HVP) is an international consortium of clinicians, geneticists, and researchers from over 30 countries, aiming to facilitate the establishment and maintenance of standards, systems, and infrastructure for the worldwide collection and sharing of all genetic variations effecting human disease. The HVP‐China Node will build new and supplement existing databases of genetic diseases. As the first batch of this effort, we have created a novel variant database of BRCA1 and BRCA2, mismatch repair genes (MMR), and APC genes for breast cancer, Lynch syndrome, and familial adenomatous polyposis (FAP), respectively, in the Chinese population using the Leiden Open Variation Database (LOVD) format. We searched PubMed and some Chinese searching engines to collect all ...

Universal CRC screening best for identifying Lynch syndrome patients

MedWire News - Gastroenterology — Wed, 07 Sep 2011 03:31:47 +0100

Universal molecular screening has greater sensitivity for detection of Lynch syndrome among colorectal cancer patients than the revised Bethesda guidelines, demonstrate study findings published in the journal Gut. (Source: MedWire News - Gastroenterology)

Screening for Lynch Syndrome in Colorectal Cancer: Are We Doing Enough?

Annals of Surgical Oncology — Wed, 31 Aug 2011 05:51:34 +0100

Conclusions Strict application of the Bethesda criteria does not lead to identification of all patients with LS. IHC and MSI testing are complementary methods and should be used in association to identify potential LS patients. Content Type Journal ArticleCategory Colorectal CancerPages 1-8DOI 10.1245/s10434-011-2014-7Authors Guillaume Canard, Department of Digestive Surgery, Hôpital Saint-Antoine, Université Pierre et Marie Curie, Paris, FranceJeremie H. Lefevre, Department of Digestive Surgery, Hôpital Saint-Antoine, Université Pierre et Marie Curie, Paris, FranceChrystelle Colas, Department of Oncogenetics, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, FranceFlorence Coulet, Department of Oncogenetics, Hôpital Pitié-Salpêtrière, ...

Validation Microsatellite Path Score in a Population-Based Cohort of Patients With Colorectal Cancer [Gastrointestinal Cancer]

Journal of Clinical Oncology — Mon, 29 Aug 2011 23:00:00 +0100

Conclusion In the general nonselected population, the MsPath score accurately predicted the probability of bearing a MSI high CRC, but it was insufficiently accurate to use for the selection of patients warranting MLH1/MSH2 mutation testing in the setting of Lynch syndrome. (Source: Journal of Clinical Oncology)

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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Lynch syndrome screening implementation: business analysis by a healthcare system.

The American Journal of Managed Care — Tue, 23 Aug 2011 18:04:02 +0100

Conclusion: The current state of evidence at the time of the study period suggests an LS screening program can be both effective in reducing mortality from CRC and cost-effective. However, direct evidence remains limited and multiple factors could threaten success of such a program. We have identified opportunities for optimizing the efficiency of available screening protocols. While there was enough evidence for our system to proceed with an LS screening program, we recognize the threats to program success and will prospectively collect outcome data supporting empirical examination of the program. PMID: 21851136 [PubMed - in process] (Source: The American Journal of Managed Care)

Six primary cancers in one lynch syndrome patient with chronic arsenic exposure

Journal of Surgical Oncology — Sun, 21 Aug 2011 23:00:00 +0100

(Source: Journal of Surgical Oncology)

SEOM clinical guidelines for hereditary cancer

Clinical and Translational Oncology — Fri, 19 Aug 2011 15:56:48 +0100

The objective of this guideline in hereditary cancer is to summarise the current state of knowledge and make recommendations in the areas of diagnosis, prevention and treatment of hereditary cancer. Content Type Journal ArticleCategory Clinical Guides in OncologyPages 580-586DOI 10.1007/s12094-011-0701-2Authors Begoña Graña, High Risk and Cancer Prevention Unit Medical Oncology Department, Vall d’Hebron Institute of Oncology (VHIO), P. Vall d’Hebron, 119-129, ES-08035 Barcelona, SpainEnrique Lastra, Genetic Counselling Unit Medical Oncology Section, General Yagüe Hospital, Burgos, SpainGemma Llort, Genetic Counselling Unit, Valles Institute of Oncology, Sabadell-Terrassa, Barcelona, SpainJoan Brunet, Medical Oncology Department Hereditary Cancer Program, Catalan Institut of ...

New Effective And Significantly Less Costly Process May Save Lives Of Lynch Syndrome Patients

Health News from Medical News Today — Wed, 17 Aug 2011 09:00:00 +0100

People who are at risk for a certain form of colon and other types of cancer may soon have a better chance at surviving or even avoiding the diseases, thanks to a new study done by the Intermountain Clinical Genetics Institute at LDS Hospital. The Intermountain Heathcare group of scientists used sophisticated computer modeling to develop a reliable and cost-effective way to identify patients who may have Lynch syndrome, an inherited cancer syndrome that occurs in people who carry a genetic mutation in one of the DNA mismatch repair genes... (Source: Health News from Medical News Today)

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...

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Colorectal cancers with microsatellite instability display unique miRNA profiles.

Clinical Cancer Research — Sun, 14 Aug 2011 23:00:00 +0100

CONCLUSIONS: CRC tissues show distinct miRNA expression profiles compared to normal colonic mucosa. The discovery of unique miRNA expression profiles that can successfully discriminate between Lynch syndrome, sporadic MSI and sporadic MSS CRCs provides novel insights into the role of miRNAs in colorectal carcinogenesis which may contribute to the diagnosis, prognosis and treatment of this disease. PMID: 21844009 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Screening strategy ‘cost-effective’ for the Lynch syndrome

MedWire News - Gastroenterology — Fri, 12 Aug 2011 18:41:47 +0100

All patients newly diagnosed with colon cancer should be screened for the Lynch syndrome, an inherited defect that underlies around 3–5% of such cancers, US researchers believe. (Source: MedWire News - Gastroenterology)

Widespread testing for Lynch syndrome worth it?

PharmacoEconomics and Outcomes News — Thu, 11 Aug 2011 15:54:07 +0100

(Source: PharmacoEconomics and Outcomes News)

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)

Microsatellite instability analysis in uterine cavity washings as a screening tool for endometrial cancer in Lynch syndrome

Familial Cancer — Sat, 06 Aug 2011 05:53:58 +0100

Abstract Although patients with Lynch syndrome (LS) are at high risk of endometrial cancer, gynecologic screening has been poorly investigated and diagnostic value of current screening tests remains unclear. Microsatellite instability (MSI) phenotype is found in more than 90% of endometrial cancers developed in LS patients. Here we report the first two cases of unstable endometrial tumors with detection of MSI in uterine cavity washings cells. This new technique may be a promising screening tool in LS. Content Type Journal ArticlePages 1-3DOI 10.1007/s10689-011-9470-xAuthors Julie Bouquier, Université Paris Descartes, Paris, FranceHélène Blons, Université Paris Descartes, Paris, FranceCéline Narjoz, Université Paris Descartes, Paris, FranceFabrice Lécuru, Univer...

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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,...

Hereditary Colon Cancer Syndromes

Seminars in Oncology — Sun, 31 Jul 2011 23:00:00 +0100

Colon cancer is associated with a family history in up to 25% of cases. As many as 5% are associated with an established hereditary syndrome, demonstrating the profound influence of inheritable genetic mechanisms in the development of this disease. These syndromes confer a diverse spectrum of risk, age of presentation, endoscopic and histological findings, extracolonic manifestations, and modes of inheritance. As the molecular characteristics of these disorders become better described, enhanced genotype–phenotype correlations may offer a more targeted approach to diagnosis, screening, and surveillance. While the strategies for diagnosis and management of familial adenomatous polyposis (FAP) and Lynch syndrome are more established, the approach to newly recognized syndromes such as MUTYH-...

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...

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...

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Determining the frequency of de novo germline mutations in DNA mismatch repair genes

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

Conclusion De novo MMR gene mutations are uncommon causes of Lynch syndrome. (Source: Journal of Medical Genetics)

Study Shows That Screening New Colon Cancer Patients For Lynch Syndrome Would Be Cost-Effective

Health News from Medical News Today — Tue, 19 Jul 2011 10:00:00 +0100

Screening every new colon cancer patient for a particular familial disorder extends lives at a reasonable cost, say Stanford University School of Medicine researchers. The team hopes the results will encourage more medical centers to adopt widespread screening policies. Approximately 3 to 5 percent of colorectal tumors are caused by a heritable condition called Lynch syndrome, which greatly increases the odds of colon and other cancers in a person's lifetime... (Source: Health News from Medical News Today)

News From The Annals Of Internal Medicine: July 19, 2011

Health News from Medical News Today — Tue, 19 Jul 2011 08:00:00 +0100

1. Testing for the Lynch Syndrome in All Colorectal Cancer Patients Cost-effective Relatives of Those Who Test Positive Are at Increased Risk and Should Also be Tested The Lynch syndrome is the most common genetic cause of colorectal cancer and is also associated with endometrial and other types of cancer. While only three percent of colorectal cancer patients carry the gene, it has been suggested that testing for the Lynch syndrome in all patients newly diagnosed with colorectal cancer could help identify families at risk... (Source: Health News from Medical News Today)

Screening for Lynch Syndrome in Colon Cancer Patients is Cost Effective

Medical Headlines From Ivanhoe.com — Tue, 19 Jul 2011 05:00:00 +0100

(Ivanhoe Newswire) -- Screening every new colon cancer patient for a particular familial disorder extends lives at a reasonable cost, Stanford University School of Medicine researchers said. (Source: Medical Headlines From Ivanhoe.com)

Who should have genetic testing for the lynch syndrome?

Annals of Internal Medicine — Mon, 18 Jul 2011 23:00:00 +0100

Authors: Burt RW PMID: 21768586 [PubMed - in process] (Source: Annals of Internal Medicine)

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Strategies to identify the lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis.

Annals of Internal Medicine — Mon, 18 Jul 2011 23:00:00 +0100

Conclusion: Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome. Primary Funding Source: National Institutes of Health. PMID: 21768580 [PubMed - in process] (Source: Annals of Internal Medicine)

Screening new colon cancer patients for Lynch syndrome would be cost-effective, study shows

EurekAlert! - Cancer — Mon, 18 Jul 2011 04:00:00 +0100

(Stanford University Medical Center) Screening every new colon cancer patient for a particular familial disorder extends lives at a reasonable cost, say Stanford University School of Medicine researchers. The team hopes the results will encourage more medical centers to adopt widespread screening policies. (Source: EurekAlert! - Cancer)

Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40years of age and younger.

Gynecologic Oncology — Thu, 07 Jul 2011 23:00:00 +0100

CONCLUSIONS: Endometrial cancer is rare in women aged 40years or less. In this group of patients, loss of DNA MMR was associated with lower BMI, worse clinicopathologic factors, and worse outcome. These results may have implications when young women diagnosed with endometrial cancer are counseled regarding prognosis. PMID: 21742371 [PubMed - as supplied by publisher] (Source: Gynecologic Oncology)

Risk for CRC in Lynch Syndrome May Be Lower Than We ThoughtRisk for CRC in Lynch Syndrome May Be Lower Than We Thought

Medscape Today Headlines — Wed, 06 Jul 2011 14:29:00 +0100

Drs. Gil Melmed and Dermot McGovern look at the value of screening for Lynch syndrome in patients and families with young-onset colorectal cancer. Medscape Genomic Medicine (Source: Medscape Today Headlines)

Comparison of clinical schemas and morphologic features in predicting Lynch syndrome in mutation‐positive patients with endometrial cancer encountered in the context of familial gastrointestinal cancer registries

Cancer — Sun, 03 Jul 2011 15:19:12 +0100

CONCLUSIONS:Clinical screening criteria had variable efficacy for the identification of LS‐associated EC, and SGO 5%‐to‐10% criteria performed best. Characteristic pathologic features were present in a minority of patients. Although a high proportion of LS‐ECs had the MSI phenotype and were MMR deficient, the specificity of these tests and of clinical screening for LS in unselected patients with EC has been poorly described. Prospective studies to determine the optimal combination of these screening modalities are required. Cancer 2011;. © 2011 American Cancer Society. (Source: Cancer)

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The role of expanded testing for Lynch syndrome in women with endometrial cancer

CA: A Cancer Journal for Clinicians — Thu, 30 Jun 2011 23:00:00 +0100

(Source: CA: A Cancer Journal for Clinicians)

Endometrioid adenocarcinoma arising from colonic endometriosis in a Lynch syndrome patient

International Journal of Colorectal Disease — Wed, 22 Jun 2011 16:01:19 +0100

Content Type Journal ArticlePages 1-2DOI 10.1007/s00384-011-1267-8Authors Po-Chuan Chen, Division of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital and College of Medicine, No. 138, Sheng Li Road, Tainan City, Taiwan, Republic of China 70403Sheau-Chiou Chao, Department of Dermatology, National Cheng Kung University Hospital and College of Medicine, No. 138, Sheng Li Road, Tainan City, Taiwan, Republic of China 70403Keng-Fu Hsu, Department of Obstetrics and Gynecology, National Cheng Kung University Hospital and College of Medicine, No. 138, Sheng Li Road, Tainan City, Taiwan, Republic of China 70403Chung-Ta Lee, Department of Pathology, National Cheng Kung University Hospital and College of Medicine, No. 138, Sheng Li Road, Tainan City, Taiwan, Repub...

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...

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

Familial Cancer — Fri, 17 Jun 2011 11:57:49 +0100

Abstract Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron–exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations...

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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...

Pre‐ and postassessment of nurse practitioners' knowledge of hereditary colorectal cancer

Journal of the American Academy of Nurse Practitioners — Wed, 08 Jun 2011 23:00:00 +0100

Conclusion: Few NPs (39%) reported “comfortable” in identifying red flags “suspect” for Lynch syndrome. Percentage of NPs who responded correctly on each of the pretest items ranged from 17.0% to 57.1% (M= 26.2%; SD= 13.5%; 95% confidence intervals [CI] 14.9%, −37.5%). NPs who responded correctly to the same items after the educational program (posttest) ranged from 53.8% to 95% (M= 80.5%; SD= 15.3%; 95% CI 67.8%, −93.4%).Implications for practice: Genetic testing is widely available for Lynch syndrome. It is important that NPs are cognizant of the syndrome and identify patients at risk for hereditary cancer syndromes so appropriate referral and management can be instituted. (Source: Journal of the American Academy of Nurse Practitioners)

Cancer Risks Teased Out in Lynch Syndrome

Medscape Internal Medicine Headlines — Wed, 08 Jun 2011 20:19:13 +0100

Linkage of cancer risks to specific mutation sites could better inform surveillance practices. Medscape Medical News (Source: Medscape Internal Medicine Headlines)

Cancer Risks Teased Out in Lynch SyndromeCancer Risks Teased Out in Lynch Syndrome

Medscape Medical News Headlines — Wed, 08 Jun 2011 20:08:24 +0100

Linkage of cancer risks to specific mutation sites could better inform surveillance practices. Medscape Medical News (Source: Medscape Medical News Headlines)

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Screening for Lynch Syndrome in Young Colon Cancer Patients

Medscape Today Headlines — Wed, 08 Jun 2011 14:44:21 +0100

Colon cancer before the age of 50 might be an indication that the patient has Lynch syndrome; screening can identify these individuals. Medscape Medical News (Source: Medscape Today Headlines)

Screening for Lynch Syndrome in Young Colon Cancer PatientsScreening for Lynch Syndrome in Young Colon Cancer Patients

Medscape Gastroenterology Headlines — Wed, 08 Jun 2011 14:44:21 +0100

Colon cancer before the age of 50 might be an indication that the patient has Lynch syndrome; screening can identify these individuals. Medscape Medical News (Source: Medscape Gastroenterology Headlines)

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)

Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery

Gut — Sun, 05 Jun 2011 23:00:00 +0100

Conclusions Patients with Lynch syndrome with first colon cancer treated with more extensive colonic resection have a lower risk of metachronous CRC than those receiving less extensive surgery. This finding will better inform decision-making about the extent of primary surgical resection. (Source: Gut)

Study Identifies Genetic Mutations Associated With Cancer Risk For Hereditary Cancer Syndrome

Health News from Medical News Today — Sat, 04 Jun 2011 18:00:00 +0100

Among various genetic mutations for individuals with Lynch syndrome, a hereditary cancer syndrome that carries a high risk of colon cancer and an above-normal risk of other cancers, researchers have identified mutations associated with a lower cancer risk and mutations associateded with an increased risk for ovarian and endometrial cancer, according to a study in the June 8 issue of JAMA, a theme issue on cancer. The study is being published early online to coincide with the American Society of Clinical Oncology 2011 Annual Meeting... (Source: Health News from Medical News Today)

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Study identifies genetic mutations associated with cancer risk for hereditary cancer syndrome

EurekAlert! - Medicine and Health — Sat, 04 Jun 2011 04:00:00 +0100

(JAMA and Archives Journals) Among various genetic mutations for individuals with Lynch syndrome, a hereditary cancer syndrome that carries a high risk of colon cancer and an above-normal risk of other cancers, researchers have identified mutations associated with a lower cancer risk and mutations associated with an increased risk for ovarian and endometrial cancer, according to a study in the June 8 issue of JAMA, a theme issue on cancer. (Source: EurekAlert! - Medicine and Health)

Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome [Original Contribution]

JAMA — Fri, 03 Jun 2011 23:00:00 +0100

Conclusions MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years. (Source: JAMA)

Cancer Risk Assessment in Lynch Syndrome: Does the Gene Matter? [Editorial]

JAMA — Fri, 03 Jun 2011 23:00:00 +0100

(Source: JAMA)

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)

Management of young onset colorectal cancer: divergent practice in the East of England

Colorectal Disease — Tue, 31 May 2011 23:00:00 +0100

Conclusion: Many patients with young onset CRC are managed as sporadic cancers, without Lynch syndrome having been excluded. This may have implications for survival of patients and any affected relatives. A streamlined management algorithm for tumour screening and genetics referral is recommended. (Source: Colorectal Disease)

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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...

Testing Women With Endometrial Cancer to Detect Lynch Syndrome [Genetic Testing for Cancer]

Journal of Clinical Oncology — Thu, 26 May 2011 23:00:00 +0100

Conclusion IHC triage of women with endometrial cancer at any age having at least 1 FDR with a Lynch-associated cancer is a cost-effective strategy for detecting Lynch syndrome. (Source: Journal of Clinical Oncology)

Avoidance of pseudogene interference in the detection of 3′ deletions in PMS2

Human Mutation — Wed, 25 May 2011 23:00:00 +0100

AbstractLynch syndrome is characterized by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. In PMS2, detection of mutations is confounded by numerous pseudogenes. Detection of 3′ deletions is particularly complicated by the pseudogene PMS2CL, which has strong similarity to PMS2 exons 9 and 11–15, due to extensive gene conversion. A newly‐designed multiplex ligation‐dependent probe amplification (MLPA) kit incorporates probes for variants found in both PMS2 and PMS2CL. This provides detection of deletions, but does not allow localization of deletions to the gene or pseudogene. To address this, we have developed a methodology incorporating reference samples with known copy numbers of variants, and paired MLPA results with sequencing of PMS2 and PMS2CL. We tested a s...

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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Malignant fibrous histiocytoma is a rare Lynch syndrome-associated tumor in two German families

Familial Cancer — Fri, 20 May 2011 05:56:44 +0100

In conclusion, our data further support that patients with Lynch syndrome are at increased risk for rare tumors such as MFH. However, the prognosis compared to sporadic MFH seems to be favorable. Content Type Journal ArticlePages 1-5DOI 10.1007/s10689-011-9455-9Authors Angela Brieger, Medical Clinic 1, Biomedical Research Laboratory, Johann Wolfgang Goethe-University, Frankfurt am Main, GermanyKnut Engels, Senckenbergisches Institute of Pathology, Johann Wolfgang Goethe-University, Frankfurt am Main, GermanyDieter Schaefer, Institute of Humangenetics, Johann Wolfgang Goethe-University, Frankfurt am Main, GermanyGuido Plotz, Medical Clinic 1, Biomedical Research Laboratory, Johann Wolfgang Goethe-University, Frankfurt am Main, GermanyStefan Zeuzem, Medical Clinic 1, Biomedical Rese...

DNA Repair System Affects Colon Cancer Recurrence And Survival

Health News from Medical News Today — Thu, 19 May 2011 20:00:00 +0100

Colorectal cancer patients with defects in mismatch repair - one of the body's systems for repairing DNA damage--have lower recurrence rates and better survival rates than patients without such defects, according to a study published online May 19th in the Journal of the National Cancer Institute. About 15% of colorectal cancers are associated with mismatch repair defects. Some defects are caused by the inherited gene mutations found in Lynch syndrome and others occur by chance, or "sporadically... (Source: Health News from Medical News Today)

Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer

Familial Cancer — Thu, 19 May 2011 16:36:31 +0100

Abstract High level microsatellite instability (MSI-H) is a hallmark of Lynch syndrome-associated colorectal cancer (CRC). MSI-H CRC express immunogenic tumour antigens as a consequence of DNA mismatch repair deficiency-induced frameshift mutations. Consequently, frameshift antigen-specific immune responses are commonly observed in patients with Lynch syndrome-associated MSI-H CRC. Dendritic cells (DC) and macrophages play a crucial role in the induction and modulation of immune responses. We here analysed DC and macrophage infiltration in MSI-H and microsatellite-stable CRC. Sixty-nine CRC (MSI-H, n = 33; microsatellite-stable, n = 36) were examined for the density of tumour-infiltrating DC, Foxp3-positive regulatory T cells, and CD163-positive macropha...

New Mayo Clinic Test Targets Lynch Syndrome, a Risk Factor for Colon Cancer

Mayo Clinic Rochester News — Thu, 19 May 2011 16:23:22 +0100

Test Targets Lynch Syndrome, A Risk Factor For Colon Cancer

Health News from Medical News Today — Wed, 18 May 2011 17:00:00 +0100

Mayo Clinic has developed a screening procedure that could dramatically increase testing for Lynch syndrome, a hereditary genetic disorder that raises cancer risk, particularly for colorectal cancer. An estimated 3 percent of colon cancers can be attributed to Lynch syndrome. At least 80 percent of people with Lynch syndrome develop colorectal cancer, many of them before age 50. In the past, as few as 50 percent of patients who fit the profile for possible Lynch syndrome were tested before or after surgery... (Source: Health News from Medical News Today)

Early-Onset Colorectal Cancer is an Easy and Effective Tool to Identify Retrospectively Lynch Syndrome

Annals of Surgical Oncology — Wed, 18 May 2011 06:12:36 +0100

Conclusions Early age of onset is an effective method to identify retrospectively Lynch syndrome. Taking into account the location and histology features of the tumor, and the familial history of the cases, we notably increase the a priori probability of detecting a germline MMR mutation. Content Type Journal ArticlePages 1-7DOI 10.1245/s10434-011-1782-4Authors José Perea, Surgery Department, Hospital Universitario 12 de Octubre, Madrid, SpainYolanda Rodríguez, Pathology Department, Hospital Universitario 12 de Octubre, Madrid, SpainDaniel Rueda, Molecular Biology Laboratory, Hospital Universitario 12 de Octubre, Madrid, SpainJosé C. Marín, Gastroenterology Department, Hospital Universitario 12 de Octubre, Madrid, SpainJosé Díaz-Tasende, Gastroenterology Depar...

New Mayo Clinic test targets Lynch syndrome, a risk factor for colon cancer

EurekAlert! - Medicine and Health — Wed, 18 May 2011 04:00:00 +0100

(Mayo Clinic) Mayo Clinic has developed a screening procedure that could dramatically increase testing for Lynch syndrome, a hereditary genetic disorder that raises cancer risk, particularly for colorectal cancer. (Source: EurekAlert! - Medicine and Health)

Effectiveness of a colonoscopic screening programme in first‐degree relatives of patients with colorectal cancer

Colorectal Disease — Thu, 12 May 2011 18:29:28 +0100

Conclusion We detected advanced neoplasia in a considerable number of participants. Our data support colonoscopy screening in first‐degree relatives of patients with CRC at an earlier age than in the medium‐risk population. Male sex and sibling relationship were predictors of advanced neoplasia. (Source: Colorectal Disease)

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Attitudes toward childbearing and prenatal testing in individuals undergoing genetic testing for Lynch Syndrome

Familial Cancer — Thu, 12 May 2011 16:46:00 +0100

Abstract To examine attitudes toward childbearing and prenatal genetic testing among individuals at risk for Lynch Syndrome (LS), the most common type of hereditary colorectal cancer. Individuals undergoing clinical genetic testing for mismatch repair (MMR) gene mutations completed written questionnaires before and after testing. 161 of 192 (84%) eligible individuals participated in the study. Mean age was 46 years (range 20–75), 71% were female, 53% had a personal diagnosis of cancer, and 68% had children. Eighty percent worried about their children’s risk for developing cancer; however only 9% reported their decision to have children was affected by their family history of cancer. When asked whether providing prenatal testing to carriers of MMR gene mutations wa...

The Importance of Older Family Members in Providing Social Resources and Promoting Cancer Screening in Families With a Hereditary Cancer Syndrome.

The Gerontologist — Tue, 10 May 2011 23:00:00 +0100

This study evaluates the role of older family members as providers of social resources within familial network systems affected by an inherited cancer susceptibility syndrome. DESIGN AND METHODS: Respondents who previously participated in a study that involved genetic counseling and testing for Lynch syndrome and their family network members were invited to participate in a onetime telephone interview about family communication. RESULTS: A total of 206 respondents from 33 families identified 2,051 social relationships (dyads). Nineteen percent of the respondents and 25% of the network members were older (≥60 years). Younger respondents (≤59 years) were more likely to nominate older network members as providers of social resources than younger members: instrumental support (...

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...

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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...

Best way to screen for Lynch syndrome in women with endometrial cancer identified

Modern Medicine — Sun, 01 May 2011 23:00:00 +0100

NEW YORK (Reuters Health) - Screening for Lynch syndrome in women with endometrial cancer and one first-degree relative who had a Lynch-associated cancer is cost-effective, according to a new study. (Source: Modern Medicine)

Molecular diagnostics of colorectal cancer.

Archives of Pathology and Laboratory Medicine — Sat, 30 Apr 2011 23:00:00 +0100

Conclusions.-In modern pathology practice, molecular testing is a standard tool that is used to diagnose an inherited colorectal cancer predisposition syndrome (Lynch syndrome) and to help predict outcome and response to therapy for patients with advanced colorectal cancer. PMID: 21526956 [PubMed - in process] (Source: Archives of Pathology and Laboratory Medicine)

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...

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...

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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)

Evaluation of predictive models for the identification in daily practice of patients with lynch syndrome

International Journal of Cancer — Sun, 24 Apr 2011 23:00:00 +0100

AbstractThe optimal strategy for identifying patients with Lynch syndrome among newly diagnosed colorectal cancer (CRC) patients is still debated. Several predictive models (MMRpredict, PREMM1,2, MMRpro) combining personal and familial data have recently been developed to quantify the risk that a given patient with CRC carries a Lynch syndrome‐causing mutation. Their clinical applicability to CRC patients from the general population requires evaluation. We studied a consecutive series of 214 patients with newly diagnosed CRC characterized for tumor microsatellite instability (MSI), somatic BRAF mutation, MLH1 promoter methylation, and mismatch repair (MMR) gene germline mutation status. The performances of the models for identifying MMR mutation carriers (8/214, 3.7%) were evaluated and ...

Evaluation of predictive models in daily practice for the identification of patients with Lynch syndrome

International Journal of Cancer — Sun, 24 Apr 2011 23:00:00 +0100

AbstractThe optimal strategy for identifying patients with Lynch syndrome among patients with newly diagnosed colorectal cancer (CRC) is still debated. Several predictive models (e.g., MMRpredict, PREMM1,2 and MMRpro) combining personal and familial data have recently been developed to quantify the risk that a given patient with CRC carries a Lynch syndrome‐causing mutation. Their clinical applicability to patients with CRC from the general population requires evaluation. We studied a consecutive series of 214 patients with newly diagnosed CRC characterized for tumor microsatellite instability (MSI), somatic BRAF mutation, MLH1 promoter methylation and mismatch repair (MMR) gene germline mutation status. The performances of the models for identifying MMR mutation carriers (8/214, 3.7%) w...

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)

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[Lynch syndrome: Towards a multidisciplinary management of tumour screening.]

Gynecologie, Obstetrique et Fertilite — Wed, 13 Apr 2011 23:00:00 +0100

Authors: Bats AS, Cellier C, Samaha E, Laurent-Puig P, Lecuru F PMID: 21497539 [PubMed - as supplied by publisher] (Source: Gynecologie, Obstetrique et Fertilite)

Lynch Syndrome in Young-Onset Colorectal Cancer: Reassessing the Role of the MSH6 Gene

Clinical Gastroenterology and Hepatology — Sun, 10 Apr 2011 23:00:00 +0100

We have read with interest the article by Limburg et al, which assessed the frequency of Lynch syndrome (LS) in an American young-onset colorectal cancer (CRC) cohort (n = 195). LS is caused by germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2). The authors found 11 (5.6%) cases with deleterious mutations (5 MSH2, 4 MLH1, 2 MSH6). Recently, we have also analyzed the LS frequency in a Spanish early-onset CRC cohort (n = 140), identifying 11 (7.8%) germline mutations (4 MLH1, 1 MSH2, 6 MH6). The LS prevalence in our study was slightly higher and, noteworthy, MSH6 mutations were more frequent. We believe that this disparity may be because of a differential classification of variants of uncertain significance (VUS). We used bioinformatics tools to predict pathogenicity of VUS...

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...

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)