MedWorm: Hereditary Nonpolyposis Colorectal Cancer

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

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

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

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Recent Findings Highlight Research In Hereditary Nonpolyposis Colorectal Cancer

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

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

Reports from Cleveland Clinic Advance Knowledge In Colon Cancer

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

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

Annual Colonoscopy Helpful for High-Risk Cancer Group

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

No abstract available (Source: Advances in Anatomic Pathology)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Inherited Colorectal Cancer Syndromes

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

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

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

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

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

CHEK2 mutations and HNPCC-related colorectal cancer

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

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

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC

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

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

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

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

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

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

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

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

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

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

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

Aspirin Benefits People With Lynch Syndrome (HNPCC)

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

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

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

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

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

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The hMSH2 and hMLH1 Genes in Hereditary Nonpolyposis Colorectal Cancer

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

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

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

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

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

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

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

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

Cancer Risk Assessment by Rural and Appalachian Family Medicine Physicians

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Hnpcc

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

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

1940's drug targets bowel cancer gene

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Lynch Syndrome(HNPCC) - Know the Risks

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

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

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

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

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

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

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

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

Papillary serous carcinoma in situ in ovarian endometriosis in an MSH2 mutation carrier

International Journal of Gynaecology and Obstetrics — Sun, 21 Jun 2009 23:00:00 +0100

We report a unique case of noninvasive serous carcinoma that developed in an endometriotic cyst of the ovary in an MSH2 mutation carrier. (Source: International Journal of Gynaecology and Obstetrics)

Colon cancer screening practices and disclosure after receipt of positive or inconclusive genetic test results for hereditary nonpolyposis colorectal cancer

Cancer — Tue, 16 Jun 2009 23:00:00 +0100

This study compared endoscopy use and disclosure between individuals with positive and inconclusive genetic test results, within a year after results were received.Individuals with a personal history of cancer and suspected of having HNPCC participated in genetics education and counseling, underwent HNPCC testing, and received genetic test results (GCT) within a prospective cohort study. Demographic, psychosocial, and behavioral data were obtained from questionnaires and interviews completed before and after GCT.Index cases with inconclusive genetic test results were less likely to screen within 12 months. Index cases who disclosed test results to children within 6 months were more likely to screen within 12 months, controlling for mutation status. Index cases with inconclusive genetic tes...

Improvement of endometrial biopsy over transvaginal ultrasound alone for endometrial surveillance in women with Lynch syndrome

Familial Cancer — Sat, 06 Jun 2009 10:07:06 +0100

Abstract In women with hereditary non polyposis colorectal carcinoma (HNPCC) an annual gynaecological surveillance has been recommended because of an increased lifetime risk of developing endometrial and ovarian carcinoma. The aim of this study was to assess the efficacy of gynaecological surveillance with regard to endometrial and ovarian carcinoma. Included were women from families that fulfilled the revised Amsterdam criteria for HNPCC or who showed a proven mutation in one of the mismatch repair genes. An annual gynaecological surveillance was performed (transvaginal ultrasound (TVU) and CA 125 assessment). From January 2006 on, routine endometrial sampling was included. In a total number of 100 women 285 surveillance visits were performed. Among these, in 64 visits ro...

Anaplastic oligoastrocytoma in Turcot syndrome

Journal of Neuro-Oncology — Thu, 04 Jun 2009 11:19:48 +0100

We report a 72 year old woman with anaplastic oligoastrocytoma in the setting of TS. Careful analysis of tumor DNA is required to exclude the chance occurrence of a brain tumor in HNPCC kindreds and increase our understanding of the pathogenesis of the disease. Our case adds to the handful of cases published with detailed molecular data previously. Content Type Journal ArticleCategory Case ReportDOI 10.1007/s11060-009-9928-yAuthors Joachim Baehring, Yale University School of Medicine Department of Neurology 333 Cedar Street, TMP412 New Haven CT 06510 USAPei Hui, Yale University School of Medicine Department of Pathology New Haven CT USAJoseph Piepmeier, Yale University School of Medicine Department of Neurosurgery New Haven CT USASerguei I. Bannykh, Cedars Sinai Medical Center...

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A Parametric Model for Analyzing Anticipation in Genetically Predisposed Families

Statistical Applications in Genetics and Molecular Biology — Tue, 02 Jun 2009 23:09:51 +0100

Anticipation, i.e. a decreasing age-at-onset in subsequent generations has been observed in a number of genetically triggered diseases. The impact of anticipation is generally studied in affected parent-child pairs. These analyses are restricted to pairs in which both individuals have been affected and are sensitive to right truncation of the data. We propose a normal random effects model that allows for right-censored observations and includes covariates, and draw statistical inference based on the likelihood function. We applied the model to the hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome family cohort from the national Danish HNPCC register. Age-at-onset was analyzed in 824 individuals from 2-4 generations in 125 families with proved disease-predisposing mutations. ...

Four novel germline mutations in the MLH1 and PMS2 mismatch repair genes in patients with hereditary nonpolyposis colorectal cancer

International Journal of Colorectal Disease — Fri, 29 May 2009 08:16:28 +0100

Conclusion In all patients, an abnormal expression of the MMR proteins in HNPCC was related to the above novel mutations. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00384-009-0731-1Authors Mahdi Montazer Haghighi, Taleghani Hospital, Shaheed Beheshti Medical University Research Center for Gastroenterology and Liver Diseases Zip Code: 1985711151 Tehran IranRamin Radpour, University of Basel Laboratory for Prenatal Medicine and Gynecologic Oncology, Women’s Hospital/Department of Biomedicine Hebelstrasse 20 CH 4031 Basel SwitzerlandKatayoun Aghajani, Taleghani Hospital, Shaheed Beheshti Medical University Research Center for Gastroenterology and Liver Diseases Zip Code: 1985711151 Tehran IranNarges Zali, Taleghani Hospital, Shaheed Beheshti Medica...

Serous oligocystic adenoma (SOIA) of the pancreas - first reported case of a genetically fixed association in a patient with hereditary non-polyposis colorectal cancer (HNPCC).

Pathology, Research and Practice — Tue, 12 May 2009 23:00:00 +0100

We report on a 41-year-old man with a cystic lesion within the pancreatic head. Therefore, he underwent pylorus-preserving cephal duodenopancreatectomy. Pathohistologic investigation revealed a SOIA. He had a medical history significant for subtotal colectomy because of a synchronous double colonic carcinoma. Both tumor tissue specimens had been characterized for a high level of microsatellite instability (MSI) and loss of hMLH1, as well as for a corresponding germ line mutation in hMLH1 gene, leading to the diagnosis of hereditary non-polyposis associated colon cancer (HNPCC). The case is remarkable since the SOIA revealed MSI and loss of hMLH1 protein in the tumor cells that has never been reported for this tumor type. In addition, there is a rare and extraordinary association between SO...

A novel germline mutation of hMLH1 in a Korean hereditary non-polyposis colorectal cancer family.

International Journal of Oncology — Thu, 30 Apr 2009 23:00:00 +0100

We report on the case of a Korean HNPCC family with endometrial cancer, with the goal of elucidating the involvement of an MMR deficiency. Although the family history did not fulfill the Amsterdam criteria II, blood samples were subjected to genetic testing by the revised Bethesda guidelines. Immunohistochemistry and direct sequencing of the genomic DNA identified a C insertion at the 1780th base in exon 16 of hMLH1, a pathogenic mutation that has not been reported before. By this mutation, premature termination at codon 592 resulted with an estimated deletion of 21% of the C-terminus of the hMLH1 protein. For early detection of the disease, the family was examined by colonoscopy and a gynecologic examination. The expression of hMLH1 in colon tissues was analyzed by Western blot analysis. ...

A new strategy to screen MMR genes in Lynch Syndrome: HA-CAE, MLPA and RT-PCR

European Journal of Cancer — Tue, 28 Apr 2009 23:08:22 +0100

Abstract: Aims: Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant disorder that is genetically heterogeneous because of underlying mutations in mismatch repair (MMR) genes, primarily MLH1, MSH2 and MSH6. One challenge to correctly diagnose HNPCC is that the large size of the causative genes makes identification of mutations both labour intensive and expensive.Methods: Our heteroduplex analysis by capillary array electrophoresis (HA-CAE) method, previously developed to increase the throughput and allow other multi-exon genes to be scanned, has been adapted for MMR genes. The altered peak patterns were then sequenced. Furthermore, the mutational scanning was completed using the Multiplex Ligation-Dependent Probe Amplification (MLPA) test in all negative HA-CAE cases, and...

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Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging colonoscopy in hereditary nonpolyposis colorectal cancer screening

Endoscopy — Wed, 08 Apr 2009 02:02:00 +0100

Endoscopy 2009; 41: 316-322DOI: 10.1055/s-0028-1119628 Individuals carrying germline mutations in one of the genes responsible for hereditary nonpolyposis colon cancer (HNPCC) have a lifetime risk of up to 80 % of developing colorectal cancer. As there is evidence for a higher incidence of flat adenomatous precursors and because an accelerated adenoma–carcinoma sequence has been postulated for these patients, early detection of these lesions is essential. It was the aim of the present study to assess the detection rate of polypoid lesions by comparing chromocolonoscopy with standard white light colonoscopy and narrow-band imaging (NBI) colonoscopy.[...]© Georg Thieme Verlag KG Stuttgart · New YorkGet connected:Table of contents | Abstract | Full text (Source: Endo...

[Our experience with the incidence of hereditary non-polyposis colorectal cancer]

Magyar Sebeszet — Tue, 31 Mar 2009 23:00:00 +0100

CONCLUSION: 8 out of 10 pathogenic mutations were novel and published rst time by ourselves. No repeatedly occurring mutations were found in our patients. It seems that these genetic alterations are located sporadically on different exons of the involved MMR genes. Our mutation detection rate was 77 percent in the Amsterdam positive patients who were completely examined, which appears to be better than the published data in the relevant literature. Importantly, 30 percent of the mutation carrier could be missed applying only this single criteria system. In order to detect the highest number of HNPCC patients, we suggest using both the Amsterdam as well as the Bethesda Criteria. PMID: 19386570 [PubMed - indexed for MEDLINE] (Source: Magyar Sebeszet)

[Review] Management of extracolonic tumours in patients with Lynch syndrome

The Lancet Oncology — Mon, 30 Mar 2009 04:00:00 +0100

Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, is responsible for 2–3% of all colorectal cancers. Lynch syndrome is also associated with a high risk of extracolonic cancers, including endometrial, stomach, small bowel, pancreas, biliary tract, ovary, urinary tract, brain, and skin cancer. In this Review, we discuss the risks, surveillance tests, and guidelines for the management of extracolonic tumours associated with Lynch syndrome. For all types of extracolonic cancer, evidence supporting surveillance is scarce. A benefit of surveillance is evident only for endometrial cancer, where transvaginal ultrasound and endometrial sampling detect tumours in early stages. Surveillance is generally recommended for urinary tract and gastric cancer, especially in families with more t...

Knowledge about hereditary nonpolyposis colorectal cancer; mutation carriers and physicians at equal levels

BMC Medical Genetics - Latest articles — Thu, 26 Mar 2009 04:00:00 +0100

Background: Identification and adequate management of individuals at risk for hereditary nonpolyposis colorectal cancer (HNPCC) is crucial since surveillance programmes reduce morbidity and mortality. We investigated knowledge about key features of HNPCC in at risk individuals and physicians in surgery, gynecology and oncology. Methods: Data were collected using a questionnaire which was answered by 67 mutation carriers and 102 physicians from the southern Swedish health care region. The statements were related to colorectal cancer, heredity and surveillance and the physicians were also asked questions about cancer risks and surveillance strategies. Results: Both groups answered questions on colorectal cancer risk, surveillance and genetic testing well, whereas answers about inheritance ...

Study: Women and HNPCC

About.com Colon Cancer — Sat, 07 Mar 2009 05:00:00 +0100

This study looked at ways to prevent the other cancers from occurring. (Source: About.com Colon Cancer)

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Definition of HNPCC

About.com Colon Cancer — Sat, 07 Mar 2009 05:00:00 +0100

Most people have about a 6% chance of developing colon cancer at some point in their lives, usually after age 60. People with hereditary nonpolyposis colon cancer (HNPCC) have about an 80% risk of developing colon cancer, usually by age 44. Women with HNPCC also have about a 50% chance of developing uterine cancer. (Source: About.com Colon Cancer)

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer.

World Journal of Gastroenterology — Sat, 28 Feb 2009 05:00:00 +0100

CONCLUSION: Scientific and rational detection strategy can improve the detection rate of HNPCC. Based on traditional molecular genetics and combined with epigenetics, multiple detection methods can accurately diagnose HNPCC. PMID: 19248199 [PubMed - in process] (Source: World Journal of Gastroenterology)

A new strategy to screen MMR genes in Lynch Syndrome: HA-CAE, MLPA and RT-PCR.

European Journal of Cancer — Thu, 26 Feb 2009 05:00:00 +0100

Authors: Perez-Cabornero L, Velasco E, Infante M, Sanz D, Lastra E, Hernández L, Miner C, Duran M AIMS: Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant disorder that is genetically heterogeneous because of underlying mutations in mismatch repair (MMR) genes, primarily MLH1, MSH2 and MSH6. One challenge to correctly diagnose HNPCC is that the large size of the causative genes makes identification of mutations both labour intensive and expensive. METHODS: Our heteroduplex analysis by capillary array electrophoresis (HA-CAE) method, previously developed to increase the throughput and allow other multi-exon genes to be scanned, has been adapted for MMR genes. The altered peak patterns were then sequenced. Furthermore, the mutational scanning was completed using ...

Biopsies of colorectal clinical polyps - emergence of diagnostic information on deeper levels.

Pathology, Research and Practice — Thu, 12 Feb 2009 05:00:00 +0100

Authors: Warnecke M, Engel UH, Bernstein I, Mogensen AM, Holck S Although the occasional appearance of a normal histology of biopsies from endoscopic colorectal (CR) polyps is generally held knowledge, its prevalence has rarely been focused on, and the yield of additional sections in such cases has been previously addressed in merely four communications. Hitherto, this issue has not been discussed in the context of the clinical setting. The prime aim of this study was to evaluate the yield of step sectioning CR biopsies, considered non-diagnostic (non-diagnostic biopsies (NDB)) on routine sections. The results are correlated with the indications for endoscopy. Additionally, an appropriate, cost-effective approach for handling NDB was sought. Biopsies from 480 clinical polyps were prosp...

An Interstitial Deletion at 3p21.3 Results in the Genetic Fusion of MLH1 and ITGA9 in a Lynch Syndrome Family.

Clinical Cancer Research — Sun, 01 Feb 2009 05:00:00 +0100

CONCLUSIONS: This is the first description of a functional gene fusion of the human MLH1 gene, resulting in the loss of mismatch repair capabilities. The MLH1*ITGA9 fusion allele, together with deletions of the AP20 region, presumably defines a novel subclass of Lynch syndrome patients, which results in an extended tumor spectrum known from hereditary nonpolyposis colorectal cancer and Muir-Torre syndrome patients. PMID: 19188145 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

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Microsatellite instability in the evaluation of hereditary nonpolyposis colorectal cancer

Current Colorectal Cancer Reports — Thu, 29 Jan 2009 08:03:03 +0100

Abstract Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for most hereditary colorectal cancers. The detection of families with HNPCC enables disease surveillance and clinical management, which significantly reduce morbidity and mortality. Mutations in DNA mismatch repair (MMR) genes underlie HNPCC and cause microsatellite instability (MSI). Although screening for pathogenic mutations in DNA MMR genes is time consuming and costly, MSI-based molecular diagnosis improves HNPCC diagnosis, which was once based on clinical characteristics and family history alone. Patients selected for MSI testing usually fulfill the Bethesda criteria. Tumor MSI status with tissue immunohistochemistry staining directs further genetic evaluation, including sequencing of MMR genes or m...

Sporadic breast, ovarian, or uterine cancers as risk factors for colorectal cancer

Current Colorectal Cancer Reports — Thu, 29 Jan 2009 08:03:01 +0100

Abstract Sporadic colorectal, breast, endometrial, and ovarian cancers are common human malignancies. Not surprisingly, epidemiologic studies have identified multiple shared risk factors, including obesity, low exercise levels, and possibly hormonal (particularly estrogen) modulation. In addition, unlike hereditary nonpolyposis colorectal cancer syndrome, in which colorectal, endometrial, and ovarian cancers may occur because of a germline mutation in important mismatch repair genes, sporadic versions of these cancers may develop because of shared epigenetic alterations. These changes may be useful predictors of clinical outcome and response to disease-specific therapies. Content Type Journal ArticleDOI 10.1007/s11888-009-0004-yAuthors Crystal S. DenlingerDavid S. Wein...

Family communication, genetic testing and colonoscopy screening in hereditary non-polyposis colon cancer: a qualitative study

Psycho-Oncology — Wed, 28 Jan 2009 05:00:00 +0100

Conclusions: The family context and the experience of the family history can have an impact on communication, genetic testing and screening in HNPCC and this should be explored during counselling. Some individuals might benefit from support in communicating with relatives about genetic risk. Ways of improving the individual's experience of colonoscopy should also be examined. Copyright © 2009 John Wiley & Sons, Ltd. (Source: Psycho-Oncology)

Genetic variants in MUTYH are not associated with endometrial cancer risk

BioMed Central — Mon, 26 Jan 2009 05:00:00 +0100

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant inherited predisposition to a number of epithelial cancers, most notably colorectal and endometrial cancer. Outside of the context of Lynch syndrome there is little evidence for an autosomal dominant or recessive condition that predisposes to endometrial cancer. Recently, genetic variants in MUTYH have been associated with a recessive form of colorectal cancer, known as MUTYH associated polyposis or MAP. MUTYH is involved in base excision repair of DNA lesions and as such a breakdown in the fidelity of this process would necessarily not be predicted to result in a specific disease. At present there is little information about the role of MUTYH in other types of cancer and only one rep...

MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer

European Journal of Human Genetics — Wed, 21 Jan 2009 05:00:00 +0100

MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer European Journal of Human Genetics advance online publication, January 21, 2009. doi:10.1038/ejhg.2008.239 Authors: Stuart G Reeves, Cliff Meldrum, Claire Groombridge, Allan D Spigelman, Janina Suchy, Grzegorz Kurzawski, Jan Lubinski, Patrick McElduff & Rodney J Scott (Source: European Journal of Human Genetics)

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Evidence of tumor microsatellite instability in gastric cancer with familial aggregation

Familial Cancer — Sat, 17 Jan 2009 08:58:15 +0100

Abstract About 90% of gastric cancer (GC) cases appear in a sporadic setting. Nonetheless, in high incidence areas high familial aggregation rates have been recently described. Microsatellite instability (MSI) is thought to be an important molecular phenotype both in sporadic GC and in tumors of the HNPCC spectrum. The aim of this study was to assess the frequency of MSI in GC with familial aggregation. Five quasimonomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21 and NR-27) were analyzed in 250 GC patients. Seventy-five patients (30%) had at least one-first-degree family member affected by GC and 63 patients (25.2%) showed MSI. The frequency of MSI was significantly higher in patients with a positive family history of GC (38.7%) compared to patients with othe...

Nuclear import of human MLH1, PMS2, and MutL[alpha]: Redundancy is the key

Molecular Carcinogenesis — Thu, 15 Jan 2009 05:00:00 +0100

DNA mismatch repair maintains genomic stability by correcting errors that have escaped polymerase proofreading. Defects on mismatch repair genes lead to an increased mutation rate, microsatellite instability and predisposition to human non-polyposis colorectal cancer (HNPCC). Human MutL[alpha] is a heterodimer formed by the interaction of MLH1 and PMS2 that coordinates a series of key events in mismatch repair. It has been proposed that nuclear import of MutL[alpha] may be the first regulatory step on the activation of the mismatch repair pathway. Using confocal microscopy and mismatch repair deficient cells, we have identified the sequence determinants that drive nuclear import of human MLH1, PMS2, and MutL[alpha]. Transient transfection of the individual proteins reveals that MLH1 has a ...

[Genetic Testing for Cancer] Role for Genetic Anticipation in Lynch Syndrome

Journal of Clinical Oncology — Thu, 15 Jan 2009 05:00:00 +0100

Conclusion The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need to initiate surveillance programs at young age. It should also stimulate research into the genetic mechanisms that determine age at onset and whether the genetic instability that characterizes Lynch syndrome can be linked to anticipation. (Source: Journal of Clinical Oncology)

Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum

Familial Cancer — Thu, 08 Jan 2009 09:07:14 +0100

Abstract Hereditary nonpolyposis colorectal cancer (HNPCC) is primarily linked to colorectal and endometrial cancer, but is associated with a broad tumor spectrum. Though not formally part of the syndrome, occasional sarcomas have been reported in individuals with HNPCC. We used the national Danish HNPCC-register to identify HNPCC families in which sarcomas had been diagnosed. Fourteen sarcomas were identified in families with mutations in MSH2, MSH6, and MLH1. The median age at sarcoma diagnosis was 43 (15–74) years. Soft tissue sarcomas predominated followed by uterine sarcomas and eight histopathological subtypes were represented with recurrent diagnoses of liposarcoma, leiomyosarcoma, and carcinosarcoma. Tumor tissue from eight cases was available for analysis of...

Breast cancer immunohistochemistry can be useful in triage of some HNPCC families

Familial Cancer — Mon, 05 Jan 2009 06:45:43 +0100

Abstract Immunohistochemistry of tumour samples is increasingly used in the triage of families where hereditary non-polyposis colorectal cancer (HNPCC) due to mismatch repair defects is suspected. Usually, this is undertaken in tumours that are a recognised part of the spectrum of HNPCC-related cancers e.g. colon or endometrial cancers. Although breast cancers are not classed as part of this spectrum, this study examined the extent to which some breast tumours do arise by the mismatch repair pathway in these families. This may have clinical utility in families where an individual with a ‘classic HNPPC-related’ tumour is not available for evaluation. Immunohistochemistry of a breast tumour may identify an individual in whom germline mutation testing is worthwhile. Con...

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Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation-negative familial ovarian cancers

Cancer — Tue, 30 Dec 2008 05:00:00 +0100

The objective of this study was to determine the incidence of HNPCC-related gene mutations in patients with familial ovarian cancer who previously tested negative for BRCA1 and BRCA2 gene mutations.Seventy-seven probands were identified who had familial ovarian cancer and negative BRCA gene mutation testing. Their pedigrees were analyzed for HNPCC syndrome. DNA samples underwent gene sequencing and Southern blot analysis for mutations in the 3 most common HNPCC-associated genes: mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) with reflex testing for MSH6 if tests for the first 2 genes were negative.None of the probands met Amsterdam criteria for the clinical diagnosis of HNPCC. DNA testing revealed 2 patients (2.6%) with deleterious mutations in the MSH2 gene. An additional 8 patients (10....

MLH1 promoter germline-methylation in selected probands of Chinese hereditary non-polyposis colorectal cancer families.

World Journal of Gastroenterology : WJG — Fri, 26 Dec 2008 17:30:33 +0100

CONCLUSION: Methylation phenotype of MLH1 gene is correlated with microsatellite phenotype of MMR genes, especially with MSI-H. Exhaustive-methylation of MLH1 gene can silence the expression of MLH1 protein. MLH1 promoter methylation analysis is a promising tool for molecular genetics screening for HNPCC. PMID: 19109866 [PubMed - as supplied by publisher] (Source: World Journal of Gastroenterology : WJG)

Three new nonsense mutations of MLH1 and MSH2 genes in Korean families with hereditary nonpolyposis colorectal cancer.

Cancer Genetics and Cytogenetics — Wed, 24 Dec 2008 10:47:31 +0100

Authors: Yoon S, Park TS, Kim NK, Lee KA, Kim J, Song J, Kim BY, Choi JR Hereditary nonpolyposis colorectal cancer (HNPCC) (MIM #114500), also called Lynch syndrome, is an autosomal dominantly inherited cancer syndrome accounting for 1-5% of all colorectal cancer cases. In a study of three Korean families with HNPCC consistent with the revised Bethesda criteria, DNA testing revealed three novel HNPCC germline mutations in two genes: namely, MLH1, with an insertion resulting in a frameshift and a premature stop codon; MSH2, with a deletion at nucleotide 633, exon 3, which results in stop of translation at codon 213; and MSH2, with a deletion at nucleotide 1413, exon 9, resulting in a frameshift and a premature stop codon. In the first two families, there were splice mutations at c.2006-...

Turcot Syndrome (Glioma Polyposis): A Case Report.

Southern Medical Journal — Sun, 07 Dec 2008 08:40:34 +0100

Turcot syndrome (glioma polyposis) is a rare hereditary disorder characterized by the association of colonic polyposis with primary tumors of the central nervous system. These tumors can develop almost a decade apart. The case of a 27-year-old male diagnosed with Turcot syndrome following autopsy is reported. Based on the genetic mutations, patients with Turcot syndrome are classified into the adenomatous polyposis coli (APC) group or hereditary nonpolyposis colon cancer (HNPCC) group. The article highlights the contrasting features of the two groups.Page: 1273DOI: 10.1097/SMJ.0b013e3181883853Authors: Sarin, Sanjay MD; Bernath, Albert MD (Source: Southern Medical Journal)

Hereditary nonpolyposis colorectal cancer - diagnostic strategies and their implications

Gastroenterology and Liver Diseases Specialist Library - Colon and rectum — Tue, 02 Dec 2008 10:23:07 +0100

A structured abstract written by CRD reviewers. (Source: Gastroenterology and Liver Diseases Specialist Library - Colon and rectum)

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Novel approaches in evaluation of pathogenicity of single-base exonic germline changes involving the mismatch repair genes MLH1 and MSH2 in diagnostics of Lynch syndrome.

Neoplasma — Thu, 13 Nov 2008 15:13:24 +0100

Authors: Gerykova-Bujalkova M, Krivulcik T, Bartosova Z Germline defects in the DNA mismatch repair genes MLH1 and MSH2 are the major cause of hereditary nonpolyposis colon cancer (HNPCC), also called Lynch syndrome. Detection of inherited pathogenic change in their DNA sequence in HNPCC families allows for identification of asymptomatic individuals who require appropriate medical surveillance. However, evaluation of clinical significance of identified DNA alteration is not always straight-forward and some changes maybe classified incorrectly depending on the method used. The aim of this review is to summarize rationale, practice and pitfalls in the characterization of substitutions localized in the exons and outline new experimental and in silico approaches used to determine mutation ...

HNPCC-associated synchronous early-stage signet-ring cell carcinomas of colonic origin. A comparative morphological and immunohistochemical study of an intramucosal and a submucosal example

Virchows Archiv — Tue, 11 Nov 2008 07:58:44 +0100

Abstract Signet-ring cell carcinoma (SRCC) developing in the colorectum (CR) is infrequently identified at an early stage (no deeper than submucosa). Most such examples involve the submucosa. Merely 13 cases of intramucosal CR SRCC are at hand. We recently had the opportunity to study a specimen with two synchronous early-stage SRCC, developed in a 65-year-old hereditary nonpolyposis colorectal cancer male patient with a known disease-causing mutation in MLH1. A right hemicolectomy specimen comprised a 15-mm intramucosal cecal lesion, featuring zones of conventional tubular adenoma and intraepithelial SRCC as well as tumor cells multifocally permeating the lamina propria and a 12-mm submucosally expanding SRCC of the ascending colon. The intramucosal and intraepithelial as...

[Dna: Replication, Repair, Recombination, and Chromosome Dynamics] Hereditary Cancer-associated Missense Mutations in hMSH6 Uncouple ATP Hydrolysis from DNA Mismatch Binding

Journal of Biological Chemistry — Fri, 07 Nov 2008 05:00:00 +0100

Hereditary nonpolyposis colorectal cancer is caused by germline mutations in DNA mismatch repair genes. The majority of cases are associated with mutations in hMSH2 or hMLH1; however, about 12% of cases are associated with alterations in hMSH6. The hMSH6 protein forms a heterodimer with hMSH2 that is capable of recognizing a DNA mismatch. The heterodimer then utilizes its adenosine nucleotide processing ability in an, as of yet, unclear mechanism to facilitate communication between the mismatch and a distant strand discrimination site. The majority of reported mutations in hMSH6 are deletions or truncations that entirely eliminate the function of the protein; however, nearly a third of the reported variations are missense mutations whose functional significance is unclear. We analyzed seve...

Psychosocial outcome following genetic risk counselling for familial colorectal cancer. A comparison of affected patients and family members.

Clinical Genetics — Thu, 30 Oct 2008 07:46:17 +0100

Authors: Keller M, Jost R, Haunstetter C, Sattel H, Schroeter C, Bertsch U, Cremer F, Kienle P, Tariverdian M, Kloor M, Gebert J, Brechtel A Few studies have reported prospective data on psychosocial outcomes after genetic counselling in families with suspected hereditary non-polyposis colorectal cancer (HNPCC). This prospective study examines the impact of multidisciplinary risk counselling on the psychosocial outcome of 139 affected cancer patients and 233 family members without cancer at risk for HNPCC. Participants completed questionnaires specific to HNPCC before and 8 weeks after attending the familial cancer clinic. Affected patients' levels of distress were closely related to their health status and exceeded that of unaffected individuals, as did worry regarding their relatives...

Adenoma-infiltrating Lymphocytes (AILs) are a Potential Marker of Hereditary Nonpolyposis Colorectal Cancer.

The American Journal of Surgical Pathology — Tue, 28 Oct 2008 10:37:00 +0100

Page: 1661DOI: 10.1097/PAS.0b013e31816ffa80Authors: Polydorides, Alexandros D. MD, PhD *; Mukherjee, Bhramar PhD +; Gruber, Stephen B. MD, PhD, MPH ++ [S] [//]; McKenna, Barbara J. MD *; Appelman, Henry D. MD *; Greenson, Joel K. MD * (Source: The American Journal of Surgical Pathology)

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[Cancer Diagnostics] Multiplex SNaPshot Genotyping for Detecting Loss of Heterozygosity in the Mismatch-Repair Genes MLH1 and MSH2 in Microsatellite-Unstable Tumors

Clinical Chemistry — Tue, 28 Oct 2008 04:00:00 +0100

Conclusions: Our SNP-based method for detecting LOH in MLH1 and MSH2 is simple to perform with instruments available in most clinical genetics laboratories. It can be a valuable addition to protocols now used to guide mutational screening of patients with suspected HNPCC. (Source: Clinical Chemistry)

New Tool Helps Patients Decide on Genetic Testing for Colorectal Cancer

Medscape Pathology Headlines — Mon, 20 Oct 2008 14:45:29 +0100

A decision aid has been developed that is designed to help patients determine whether or not genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC) would be helpful for them. Reuters Health Information (Source: Medscape Pathology Headlines)

MethyQESD, a robust and fast method for quantitative methylation analyses in HNPCC diagnostics using formalin-fixed and paraffin-embedded tissue samples

Laboratory Investigation AOP — Mon, 20 Oct 2008 04:00:00 +0100

Authors: Marcus Bettstetter, Stefan Dechant, Petra Ruemmele, Corinna Vogel, Katrin Kurz, Monika Morak, Gisela Keller, Elke Holinski-Feder, Ferdinand Hofstaedter & Wolfgang Dietmaier (Source: Laboratory Investigation AOP)

Colonic Adenomatous Polyposis Syndromes: Clinical Management

Clinics in Colon and Rectal Surgery — Wed, 15 Oct 2008 14:16:29 +0100

Clinics in Colon and Rectal Surgery 2008; 21: 256-262DOI: 10.1055/s-0028-1089940ABSTRACTColorectal cancer is one of the major causes of cancer deaths in both men and women. It is estimated that 5 to 10% of patients with colorectal cancer have an inherited germline mutation that predisposes them to cancer. Hereditary colorectal cancer syndromes can be divided into those associated with colonic polyposis – familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (aFAP), and associated polyposis (MAP), and those not associated with colonic polyposis – hereditary nonpolyposis colon cancer (HNPCC). The hereditary polyposes are usually easier to diagnose than HNPCC, but their higher penetrance and variable phenotype pose some difficult problems in management an...

Extracolonic Manifestations of Hereditary Colorectal Cancer Syndromes

Clinics in Colon and Rectal Surgery — Wed, 15 Oct 2008 14:16:29 +0100

Clinics in Colon and Rectal Surgery 2008; 21: 263-272DOI: 10.1055/s-0028-1089941ABSTRACTFamilial colorectal adenocarcinoma (CRC) accounts for ~15 to 20% of CRC. Of these, hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) represent the most common hereditary syndromes associated with CRC, followed by other less common diseases including juvenile polyposis (JP) and Peutz–Jeghers syndrome (PJS). Extracolonic manifestations are common in each of these syndromes having significant implications for surveillance and management in at-risk individuals. The authors review the most common and clinically relevant extracolonic manifestations for each of these syndromes focusing on incidence, presentation, genotype/phenotype correlations, and management (in...

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[Hereditary colorectal cancer.]

Der Chirurg — Wed, 15 Oct 2008 04:00:00 +0100

Authors: Möslein G One of the main challenges in the clinical management of familial colorectal cancer (CRC) remains the overlap of syndromes with different underlying genetic causes and the differentiated risk management of colorectal and associated malignancies. The Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is characterized by the development of colorectal, endometrial, gastric and other cancers and is caused by a mutation in one of the mismatch repair (MMR) genes. Microsatellite instability (MSI) and/or immunohistochemistry (IHC) are important prognostic factors and may predict the response to chemotherapy. Familial adenomatous polyposis (FAP) may be seen as a counterpart to Lynch syndrome, responsible for <1% of all CRC cases. Recently the MUTYH gen...

Mismatch repair gene mutations in Chinese HNPCC patients

Cytogenetic and Genome Research — Tue, 14 Oct 2008 14:51:30 +0100

Cytogenet Genome Res 122:22-27 (2008) (DOI:10.1159/000151312) (Source: Cytogenetic and Genome Research)

Report on de-novo mutation in the MSH2 gene as a rare event in hereditary nonpolyposis colorectal cancer.

European Journal of Gastroenterology & Hepatology — Thu, 09 Oct 2008 12:33:03 +0100

Page: 1101DOI: 10.1097/MEG.0b013e328305e185Authors: Morak, Monika a b; Laner, Andreas b; Scholz, Michael c; Madorf, Trisari a[latin sharp s]; Holinski-Feder, Elke a b (Source: European Journal of Gastroenterology & Hepatology)

[Adenocarcinoma of the rectum in a 14-year-old.]

Archives de Pediatrie — Wed, 08 Oct 2008 04:00:00 +0100

We report the case of a 14-year-old girl having a Dukes D adenocarcinoma of the rectum with peritoneal extension and bone metastases. PMID: 18848439 [PubMed - as supplied by publisher] (Source: Archives de Pediatrie)

Survival of hereditary non-polyposis colorectal cancer patients compared with sporadic colorectal cancer patients

BioMed Central — Fri, 19 Sep 2008 04:00:00 +0100

Background: Patients with hereditary non-poliposys colorectal cancer (HNPCC) have better prognosis than sporadic colorectal cancer (CRC). Aim of our retrospective study was to compare the overall survival between sporadic CRC and HNPCC patients. Methods: We analyzed a cohort of 40 (25 females and 15 males) HNPCC cases with a hospital series comprising 573 (312 and 261 respectively) sporadic CRC observed during the period 1970-1993. In fifteen HNPCC patients we performed mutational analysis for microsatellite instability. Survival rates were calculated by Kaplan-Meier method and compared with log rank test. Results: The mean age at diagnosis of the primary CRC was 46.8 years in the HNPCC series versus 61 years in sporadic CRC group. In HNPCC group 85% had a right cancer location, vs. 57% in...

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Identification and characterization of a novel MLH1 genomic rearrangement as the cause of HNPCC in a Tunisian family: evidence for a homologous Alu-mediated recombination

Familial Cancer — Tue, 16 Sep 2008 09:34:45 +0100

Abstract High rates of early colorectal cancers are observed in Tunisia suggesting high genetic susceptibility. Nevertheless, up to now no molecular studies have been performed. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent cause of inherited colorectal cancer. It is caused by constitutional mutations in the DNA mismatch repair (MMR) genes. Here, we investigated a Tunisian family highly suspected of hereditary nonpolyposis colorectal cancer (HNPCC). Six patients were diagnosed with a colorectal or an endometrial cancer at an early age, including one young female who developed a colorectal cancer at 22 years and we tested for germline mutations in MMR genes. MMR genes were tested for rearrangements by MLPA (MLH1, MSH2) and the presence of point...

Gynecologic cancers associated with Lynch syndrome/HNPCC

Clinical and Translational Oncology — Sat, 13 Sep 2008 08:05:17 +0100

Abstract Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant inherited cancer susceptibility syndrome caused by a germline mutation in one of the deoxyribonucleic acid (DNA) mismatch repair genes. It is associated with early onset of cancer (age younger than 50 years) and the development of multiple cancer types, particularly colon and endometrial cancer. Women with Lynch syndrome have a 40–60% risk of endometrial cancer, which equals or exceeds their risk of colorectal cancer. In addition, they have a 12% risk of ovarian cancer. Despite limited information on the efficacy of surveillance in reducing endometrial and ovarian cancer risk in women with Lynch syndrome, the current gynecologic cancer screening guidelines include annual en...

Genetic Epidemiology Studies in Hereditary Non-Polyposis Colorectal Cancer

Springer protocols feed by Cancer Research — Fri, 12 Sep 2008 04:00:00 +0100

Genetic epidemiology studies in hereditary non-polyposis colorectal cancer (HNPCC) have the potential to radically improve assessment of disease risk such that more individualised information can be provided to patients susceptible to developing disease. Studies of HNPCC initially focused on disease associations and the definition of the disease and its association with different cancers within the context of an inherited predisposition. With the identification of the genetic basis of HNPCC, new insights into the disease have been forthcoming and many advances in our understanding have been made. There have been many reports examining potential modifier genes in HNPCC, yet the results remain controversial as many findings have not been replicated and therefore no clear consensus as to the ...

MSH2 missense mutations and HNPCC syndrome: pathogenicity assessment in a human expression system

Human Mutation — Tue, 09 Sep 2008 04:00:00 +0100

Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is associated with germline mutations in one of several MisMatch Repair (MMR) genes. An increasing proportion (20-25%) of the reported MSH2 variants consists of single amino-acid substitution with uncertain disease-causing significance. The present study was undertaken to functionally characterize 3 MSH2 nontruncating variants: p.Gly162Arg (c.484G>C), p.Asp167His (c.499G>C) and p.Arg359Ser (c.1077A>T). Missense alterations, were assessed in a human system for expression/stability and for the ability to heterodimerize with MSH6 and correctly localize into the nucleus. Functional assays results were correlated with clinical and genetic features indicative of HNPCC as MicroSatellite-Instability (MSI), abnormalities of MMR gene expression in t...

Identification in Daily Practice of Patients With Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer): Revised Bethesda Guidelines-Based Approach Versus Molecular Screening

The American Journal of Gastroenterology — Wed, 27 Aug 2008 04:00:00 +0100

CONCLUSIONS: The revised Bethesda guidelines did not identify all HNPCC cases in our series. The molecular approach identified all HNPCC patients with MSI-positive tumors, increasing the workload for germline testing only slightly. (Am J Gastroenterol 2008;103:1[ndash]11) (Source: The American Journal of Gastroenterology)

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Recurring MLH1 deleterious mutations in unrelated Chinese Lynch syndrome families in Singapore

Familial Cancer — Sun, 24 Aug 2008 20:15:45 +0100

Abstract Lynch syndrome is an autosomal dominant disorder due to mutations in DNA mismatch repair genes, causing young onset colorectal cancer and extra-colonic cancers such as endometrial and stomach cancers. We genotyped MLH1 and MSH2 in patients suspected to have Lynch syndrome and correlated patient clinical characteristics and family history with deleterious mutations. Eighty-five unrelated patients participated. Comprehensive sequencing was performed for MLH1 and MSH2, including all coding regions, splice-site junctions and promoter regions. Of the 29 different mutations found, 11 were deleterious, of which 10 were in MLH1 and 1 in MSH2. Three recurring MLH1 deleterious mutations were found in two unrelated Chinese patients each, and haplotype analysis suggested common ...

Systems Medicine LLC (SML) Uses OmniComm Systems, Inc. For Electronic Data Capture (EDC) In A Phase II Oncology Study

Cancer / Oncology News From Medical News Today — Fri, 22 Aug 2008 07:00:00 +0100

OmniComm Systems, Inc. (OTCBB: OMCM), a leader in integrated EDC solutions for clinical trials, today announced that the company is providing EDC software and services for a Phase II trial in BRCA 1/2 and HNPCC patients sponsored by the Tucson Arizona based biotech, Systems Medicine LLC (SML). SML initially began its relationship with OmniComm through OmniComm's CRO Preferred Program™ and then selected OmniComm as its EDC vendor of choice for their Phase II study. (Source: Cancer / Oncology News From Medical News Today)

OmniComm Systems, Inc.: Systems Medicine LLC (SML) Uses OmniComm Systems, Inc. for Electronic Data Capture (EDC) in a Phase II Oncology Study

Market Wire - Pharmaceuticals and Biotech — Wed, 20 Aug 2008 19:55:00 +0100

FT. LAUDERDALE, FL (MARKET WIRE) OmniComm Systems, Inc. (OTCBB: OMCM), a leader in integrated EDC solutions for clinical trials, today announced that the company is providing EDC software and services for a Phase II trial in BRCA 1/2 and HNPCC patients sponsored by the Tucson Arizona based biotech, Systems Medicine LLC (SML). SML initially began its relationship with OmniComm through OmniComm's CRO Preferred Program(TM) and then selected OmniComm as its EDC vendor of choice for their Phase II study. (Source: Market Wire - Pharmaceuticals and Biotech)

Editorial Comment on: Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum.

European Urology — Tue, 12 Aug 2008 04:00:00 +0100

Authors: Burger M PMID: 18715704 [PubMed - as supplied by publisher] (Source: European Urology)

Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum.

European Urology — Tue, 12 Aug 2008 04:00:00 +0100

CONCLUSIONS: The recognized urologic tumor spectrum in HNPCC includes upper tract tumors. However, in order not to overlook a hereditary cancer, urologists should be aware of the possible urological malignancies associated with HNPCC (i.e., prostate and testicular carcinomas) and evaluate appropriately anyone they feel are at high risk of underlying HNPCC based on set clinical criteria. PMID: 18715695 [PubMed - as supplied by publisher] (Source: European Urology)

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Editorial Comment on: Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum.

European Urology — Tue, 12 Aug 2008 04:00:00 +0100

Authors: Mongiat-Artus P PMID: 18715693 [PubMed - as supplied by publisher] (Source: European Urology)

Which strategy holds most promise for women with HNPCC?

Inpharma — Mon, 11 Aug 2008 06:12:18 +0100

(Source: Inpharma)

Which strategy holds most promise for women with HNPCC?

PharmacoEconomics and Outcomes News — Mon, 11 Aug 2008 06:11:35 +0100

(Source: PharmacoEconomics and Outcomes News)

Which strategy holds most promise for women with HNPCC?

PharmacoEconomics & Outcomes News — Sat, 09 Aug 2008 09:24:59 +0100

Page: 13 (Source: PharmacoEconomics & Outcomes News)

Which strategy holds most promise for women with HNPCC?

Inpharma Weekly — Sat, 09 Aug 2008 09:24:50 +0100

Page: 5 (Source: Inpharma Weekly)

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[Clinical Follow-up and Presence of Visceral Tumors in 12 Patients With Sebaceous Gland Tumors.]

Actas Dermo-Sifiliograficas — Thu, 07 Aug 2008 14:25:11 +0100

CONCLUSIONS: It is essential to rule out the presence of Muir-Torre syndrome in patients with sebaceous gland tumors. The use of new techniques such as immunohistochemistry or detection of microsatellite instability may help to identify families at increased risk of Muir-Torre syndrome. PMID: 18682166 [PubMed - in process] (Source: Actas Dermo-Sifiliograficas)

Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome.

The Surgical Clinics of North America — Fri, 01 Aug 2008 04:00:00 +0100

This article reviews the clinical and genetic characteristics of FAP and Lynch syndrome, recommended screening and surveillance practices, and appropriate surgical and nonsurgical interventions. PMID: 18672142 [PubMed - in process] (Source: The Surgical Clinics of North America)

Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation.

American Journal of Obstetrics and Gynecology — Fri, 01 Aug 2008 04:00:00 +0100

CONCLUSION: Genetic counseling and testing for the MSH2 A636P mutation is indicated for Ashkenazi Jewish women with an endometrial cancer, especially if the cancer is detected before the age of 70 years in women with a personal or family history of colorectal cancer. PMID: 18674656 [PubMed - in process] (Source: American Journal of Obstetrics and Gynecology)

Hereditary ovarian cancer.

Critical Reviews in Oncology Hematology — Wed, 23 Jul 2008 04:00:00 +0100

Authors: Russo A, Calò V, Bruno L, Rizzo S, Bazan V, Di Fede G At least 10% of ovarian tumors are hereditary and associated with highly penetrant, autosomal, dominant genetic predisposition. Three clinical manifestations of hereditary ovarian cancer have been identified: site-specific ovarian cancer, hereditary breast and/or ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. BRCA germline mutations account for more than 90% of all hereditary epithelial ovarian tumors whereas most of the remaining 10% are caused by MLH1 and MSH2 mutations, which are susceptibility genes of HNPCC. Genetic testing is available for each of the three hereditary syndromes above mentioned. The recommendations for OC surveillance in high-risk women having a strong fami...

[Endometrial Cancer in HNPCC syndrome.]

Journal de Gynecologie, Obstetrique et Biologie de la Reproduction — Mon, 21 Jul 2008 04:00:00 +0100

The objective of this review was to update data on endometrial cancers of HNPCC syndrome. Endometrial cancers of the HNPCC syndrome are characterized by a younger age at diagnosis (46-48 year old), and a higher cumulative risk along life (30% at 70 years). Complex atypical hyperplasia seems to occur before the cancer, but the transition between precursors and cancer seems to be short. Histology of endometrial cancers of the HNPCC syndrome appears quite similar to that of sporadic cases, except for non-endometrioid lesions which seem more frequent and could occur in younger women. Screening of endometrial cancer in predisposed women should associate annual clinical examination, transvaginal sonography and endometrial sampling. Unfortunately, available data on screening by sonography show th...

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Clinical features and hMSH2/hMLH1 germ-line mutations in Chinese patients with hereditary nonpolyposis colorectal cancer.

Chinese Medical Journal — Sun, 20 Jul 2008 04:00:00 +0100

CONCLUSIONS: HNPCC is a typical autosomally dominant hereditary disease, characterized by early onset, a predominance of proximal colorectal cancer, and multiple synchronous and metachronous colorectal cancers. DHPLC is a powerful tool for detecting mutations in the hMSH2 and hMLH1 genes. Mutations in the first nine exons of the hMLH1 gene were more common in Chinese patients. PMID: 18713544 [PubMed - in process] (Source: Chinese Medical Journal)

Report of a family segregating mutations in both the APC and MSH2 genes: juvenile onset of colorectal cancer in a double heterozygote

International Journal of Colorectal Disease — Wed, 16 Jul 2008 05:59:24 +0100

Abstract Background and aims Mutations in DNA mismatch repair genes are associated with high risk of digestive malignancies [hereditary non-polyposis colorectal cancer (HNPCC); Lynch syndrome]; mutations of APC and MYH are associated with classic and attenuated familial adenomatous polyposis (FAP). Although the early onset of tumors in both syndromes is characteristic of their genetic origin, pediatric malignancies remain rare. Certain reports have found familial colorectal cancer (CRC) occurring in very young patients associated with mutations in more than one gene. Materials and method A family corresponding to the Amsterdam criteria for HNPCC, including two cases of colorectal cancer before the age of 25 years, was analyzed for mutations in the MSH...

IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer

International Journal of Cancer — Fri, 11 Jul 2008 04:00:00 +0100

In this study, we further investigate the cytosine-adenine (CA) dinucleotide repeat polymorphism located near the promoter region of IGF1 and its relation to early onset CRC risk in 443 Australian and Polish MMR gene mutation carriers using DNA sequencing, Kaplan-Meier survival curves and Cox proportional hazard regression analysis. A significantly smaller number of IGF1 CA repeats was observed in the Polish patient population, which was associated with an earlier age of disease onset compared to the Australian patients. The threshold for the observed modifying effect was again shown to be in patients with 17 or less CA repeats compared to those with 18 or more. Furthermore, when MMR mutation group (i.e., MLH1 or MSH2), gender and family clustering were included in the final Cox model we o...

MLPA mutation detection in Argentine HNPCC and FAP families

Familial Cancer — Thu, 10 Jul 2008 07:20:24 +0100

Abstract Colorectal cancer (CC) is the secondary cause of death in the Western countries of which approximately 15% are considered to be hereditary. The hereditary forms are Familial Adenomatous Polyposis (FAP) and Hereditary Non Polyposis Colorectal Cancer (HNPCC) which is the commonest form. The detection of mutations in the MMR and apc related genes, allows the development of health prevention strategies. Different molecular diagnostic strategies are available for the detection of mutations in these genes, i.e. DGGE, SSCP and direct sequencing. However, deletions and duplications of one or more consecutive exons, which account for around 50% of the total alterations in MMR genes, cannot be detected by PCR based methodologies due to the non quantitative nature of these tec...

Monitoring coping style moderates emotional reactions to genetic testing for hereditary nonpolyposis colorectal cancer: a longitudinal study

Psycho-Oncology — Thu, 10 Jul 2008 04:00:00 +0100

Conclusions: Genetic counseling and testing for HNPCC do not result in long-term distress for most people. Of the variables investigated, only time and coping style have main effects on emotional reactions, and the impacts of mutation status are moderated by coping style. Psychological interventions, aimed to alleviate adverse emotional effects, were suggested for certain participants, i.e. recipients of positive or indeterminate results who are high monitors. Copyright © 2008 John Wiley & Sons, Ltd. (Source: Psycho-Oncology)

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Randomized trial of a decision aid for individuals considering genetic testing for hereditary nonpolyposis colorectal cancer risk

Cancer — Thu, 10 Jul 2008 04:00:00 +0100

Despite the potential benefits of genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC) risk, individuals can find the genetic testing decision-making process complicated and challenging. The goal of the current study was to measure the effectiveness of a tailored decision aid designed specifically to assist individuals to make informed decisions regarding genetic testing for HNPCC risk.In all, 153 individuals were randomized to receive the decision aid or a control pamphlet at the end of their first genetic counseling consultation. Of these, 109 (71.2%) completed the first questionnaire 1 week after consultation, whereas 95 (62.1%) completed the 6-month follow-up questionnaire.Although the decision aid had no significant effect on postdecisional regret or actual genetic te...

Psychological impact and associated factors after disclosure of genetic test results concerning hereditary non-polyposis colorectal cancer

Stress and Health — Wed, 09 Jul 2008 04:00:00 +0100

The purpose of this study is to elucidate the psychological impact of disclosure of genetic test results concerning hereditary non-polyposis colorectal cancer (HNPCC) and to assess factors associated with it, with particular focus on memory function. The subjects were persons who were suspected of having HNPCC and given the choice of undergoing genetic testing. The post-genetic testing psychological impact was evaluated by means of the Impact of Event Scale-Revised (IES-R), and personality tendencies and memory function were evaluated. Final data were obtained from 46 subjects. The results of the genetic testing were 'mutation-positive' in 18 subjects, 'uninformative' in 18 subjects, and 'mutation-negative' in 10 subjects. Comparison of the IES-R scores showed that they tended to be higher...

Molecular epidemiological and mutational analysis of DNA mismatch repair (MMR) genes in endometrial cancer patients with HNPCC-associated familial predisposition to cancer

Cancer Science — Wed, 09 Jul 2008 04:00:00 +0100

Recently, a high rate of endometrial cancer has been reported in women with hereditary non-polyposis colorectal cancer (HNPCC), suggesting a relationship between familial endometrial cancers and HNPCC. Familial endometrial cancers constitute only about 0.5% of all endometrial carcinomas and it is essential to examine family histories in detail. A mutational analysis of three DNA mismatch repair (MMR) genes (hMLH1, hMSH2 and hMSH6) in patients with endometrial cancer who meet our criteria for familial predisposition to HNPCC-associated endometrial cancers was performed. Mutations were detected in 18 of the 120 patients (15.0%). Most HNPCC-related endometrial cancers do not meet the New Amsterdam Criteria for HNPCC. These clinical criteria may identify only some HNPCC-associated endometrial ...

Ten recently identified associations between nsSNPs and colorectal cancer could not be replicated in German families.

Cancer Letters — Wed, 09 Jul 2008 04:00:00 +0100

Authors: Frank B, Burwinkel B, Bermejo JL, Försti A, Hemminki K, Houlston R, Mangold E, Rahner N, Friedl W, Friedrichs N, Buettner R, Engel C, Loeffler M, Holinski-Feder E, Morak M, Keller G, Schackert HK, Krüger S, Goecke T, Moeslein G, Kloor M, Gebert J, Kunstmann E, Schulmann K, Rüschoff J, Propping P, Ten non-synonymous single nucleotide polymorphisms (nsSNPs), which were recently associated with colorectal cancer risk in a comprehensive, array based study (AKAP9 M463I, DKK3 G335R, AMPD1 Q12X, LIPC L356F, PSMB9 V32I, THBS1 N700S, CA6 S90G, ASCC3 C1995S, DHX36 S416C and CPA4 G303C) were re-evaluated in the present study based on 626 German familial non-HNPCC colorectal cancer patients and 736 healthy controls. No associations of any of the 10 nsSNPs with colorectal c...

[Prevention] Prevalence of Adenomas and Hyperplastic Polyps in Mismatch Repair Mutation Carriers Among CAPP2 Participants: Report by the Colorectal Adenoma/Carcinoma Prevention Programme 2

Journal of Clinical Oncology — Tue, 08 Jul 2008 04:00:00 +0100

Conclusion Adenoma prevalence increases with age among MMR mutation carriers, whereas hyperplastic polyp prevalence is consistent. No sex differences were observed for either type of lesion. (Source: Journal of Clinical Oncology)

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Immune Response Against Frameshift-Induced Neopeptides in HNPCC Patients and Healthy HNPCC Mutation Carriers.

Gastroenterology — Tue, 08 Jul 2008 04:00:00 +0100

Authors: Speetjens FM, Kuppen PJ, Morreau H, van der Burg SH PMID: 18619460 [PubMed - as supplied by publisher] (Source: Gastroenterology)

Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors

Cancer Research — Tue, 01 Jul 2008 04:00:00 +0100

Defective mismatch repair (MMR) in humans causes hereditary nonpolyposis colorectal cancer. This genetic predisposition to colon cancer is linked to heterozygous familial mutations, and loss-of-heterozygosity is necessary for tumor development. In contrast, the rare cases with biallelic MMR mutations are juvenile patients with brain tumors, skin neurofibromas, and café-au-lait spots, resembling the neurofibromatosis syndrome. Many of them also display lymphomas and leukemias, which phenotypically resembles the frequent lymphoma development in mouse MMR knockouts. Here, we describe the identification and characterization of novel knockout mutants of the three major MMR genes, mlh1, msh2, and msh6, in zebrafish and show that they develop tumors at low frequencies. Predominantly, neuro...

Phenotypic characteristics of hereditary non-polyposis colorectal cancer by the amsterdam criteria: an asian perspective

ANZ Journal of Surgery — Sat, 28 Jun 2008 04:00:00 +0100

Conclusion: This study emphasized the significant left-sided predominance of CRC in Amsterdam I and II-defined patients from our predominantly Chinese population, in contrast to those classically described in Lynch syndrome. Amsterdam criteria thus may not be suitable for diagnosing HNPCC in Asian populations and a greater emphasis should be made towards routine molecular diagnosis of mismatch repair gene defects in suspected HNPCC patients of Asian decent. (Source: ANZ Journal of Surgery)

Reduced mRNA expression in paraffin-embedded tissue identifies MLH1- and MSH2-deficient colorectal tumours and potential mutation carriers

Virchows Archiv — Thu, 26 Jun 2008 06:05:59 +0100

In conclusion, RT-PCR allows relative quantification of MMR gene mRNA expression in formalin-fixed and paraffin-embedded tissue. Furthermore, this approach enables quantification of haploinsufficiency due to nonsense-mediated mRNA decay in normal tissue and B-lymphocytes from patients carrying MSH2 germline mutations and may be useful for identification of asymptomatic carriers of pathogenic germline mutations. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00428-008-0637-2Authors Annegret Müller, University of Göttingen Department of General Surgery Göttingen GermanyDirk Zielinski, Institute of Pathology Nordhessen and Targos Molecular Pathology GmbH Kassel GermanyNicolaus Friedrichs, University Hospital Bonn Institute of Pathology Sigmund Freud Strasse 25 5...

Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population

Familial Cancer — Fri, 20 Jun 2008 06:57:03 +0100

This study presents the population-based Danish MMR gene mutation profile, which contains 138 different MMR gene alterations. Among these, 88 mutations in 164 families are considered pathogenic and an additional 50 variants from 76 families are considered to represent variants of unknown pathogenicity. The different MMR genes contribute to 40% (MSH2), 29% (MLH1), and 22% (MSH6) of the mutations and the Danish population thus shows a considerably higher frequency of MSH6 mutations than previously described. Although 69/88 (78%) pathogenic mutations were present in a single family, previously recognized recurrent/founder mutations were causative in 75/137 (55%) MLH1/MSH2 mutant families. In addition, the Danish MLH1 founder mutation c.1667+2_1667_+8TAAATCAdelinsATTT was identified in 14/5...

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A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects

Human Mutation — Tue, 17 Jun 2008 04:00:00 +0100

Numerous unclassified variants (UVs) have been found in the mismatch repair genes MLH1 and MSH2 involved in hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Some of these variants may have an effect on pre-mRNA splicing, either by altering degenerate positions of splice site sequences or by affecting intronic or exonic splicing regulatory sequences such as exonic splicing enhancers (ESEs). In order to determine the consequences of UVs on splicing, we used a functional assay of exon inclusion. For each variant, mutant and wild-type exons to be tested were PCR-amplified from patient genomic DNA together with [sim]150 bp of flanking sequences and were inserted into a splicing reporter minigene. After transfection into HeLa cells, the effects on splicing were evaluated by R...

Phenotypic characteristics of hereditary non-polyposis colorectal cancer by the amsterdam criteria: an asian perspective

ANZ Journal of Surgery — Tue, 17 Jun 2008 02:12:54 +0100

This study examined the phenotypic characteristics of CRC in Amsterdam criteria-positive Asian patients from the ... (Source: ANZ Journal of Surgery)

Familial and genetic risk of transitional cell carcinoma of the urinary tract.

Urologic Oncology — Mon, 16 Jun 2008 04:00:00 +0100

Authors: Mueller CM, Caporaso N, Greene MH Environmental exposures, including tobacco smoke and occupational exposure to aromatic amines, have been implicated in bladder cancer etiology. However, the pathogenesis of urinary bladder transitional cell carcinoma remains incompletely defined. In epidemiologic studies, family history confers a 2-fold increase in bladder cancer risk, but it is uncertain whether this represents evidence of a genetic and/or a shared environmental basis for familial aggregation. Polymorphisms in genes involved in the metabolism of environmental toxins (e.g., NAT2) clearly modify individual susceptibility to bladder cancer. A genetic predisposition has also been suggested by case reports describing multiple-case families, and the development of bladder cancer in...

Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations

Clinical Genetics — Thu, 12 Jun 2008 12:12:10 +0100

Clinical Genetics, Volume 0, Issue 0, Page ???, November 2004. Barrow E, Alduaij W, Robinson L, Shenton A, Clancy T, Lalloo F, Hill J, Evans DG. Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations.Clin Genet 2008. © Blackwell ... (Source: Clinical Genetics)

The mismatch repair-mediated cell cycle checkpoint response to fluorodeoxyuridine

Journal of Cellular Biochemistry — Wed, 11 Jun 2008 04:00:00 +0100

The loss of DNA mismatch repair (MMR) is responsible for hereditary nonpolyposis colorectal cancer and a subset of sporadic tumors. Acquired resistance or tolerance to some anti-cancer drugs occurs when MMR function is impaired. 5-Fluorouracil (FU), an anti-cancer drug used in the treatment of advanced colorectal and other cancers, and its metabolites are incorporated into RNA and DNA and inhibit thymidylate synthase resulting in depletion of dTTP and incorporation in DNA of uracil. Although the MMR deficiency has been implicated in tolerance to FU, the mechanism of cell killing remains unclear. Here, we examine the cellular response to fluorodeoxyuridine (FdU) and the role of the MMR system. After brief exposure of cells to low doses of FdU, MMR mediates DNA damage signaling during S-phas...

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The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population

BioMed Central — Wed, 11 Jun 2008 04:00:00 +0100

Conclusions: None of the variants in hMLH1 and hMSH2 analyzed in the present study were highly associated with colorectal cancer in the Danish population. High linkage disequilibrium in the genomic regions covering hMLH1 and hMSH2, indicate that common genetic variants in the two genes in general are not involved in the development of sporadic colorectal cancer. Nevertheless, some of the rare unclassified variants in hMLH1 and hMSH2 might be involved in the development of colorectal cancer in the families where they were originally identified. (Source: BioMed Central)

A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer

Cancer — Mon, 09 Jun 2008 04:00:00 +0100

Ovarian cancer ranks fifth in both cancer incidence and mortality among women in the United States. Defects in the mismatch-repair (MMR) pathway that arise through genetic and/or epigenetic mechanisms may be important etiologically in a reasonable proportion of ovarian cancers. Genetic mechanisms of MMR dysfunction include germline and somatic mutations in the MMR proteins. Germline mutations cause hereditary nonpolyposis colorectal cancer (HNPCC), which is the third most common cause of inherited ovarian cancer after BRCA1 and BRCA2 mutations. An epigenetic mechanism known to cause inactivation of the MMR system is promoter hypermethylation of 1 of the MMR genes, mutL homolog 1 (MLH1). Various laboratory methods, in addition to clinical and histopathologic criteria, can be used to identif...

Most Patients with Colorectal Tumors at Young Age Do Not Visit a Cancer Genetics Clinic

Diseases of the Colon & Rectum — Sat, 07 Jun 2008 05:53:33 +0100

Conclusion The referral process is not optimally carried out. To deliver optimal care for patients suspected of hereditary colorectal cancer, this process must be improved with interventions focusing on patient referral by surgeons and raising awareness in nonteaching hospitals. Content Type Journal ArticleCategory Original ContributionDOI 10.1007/s10350-008-9345-xAuthors Lucia I. H. Overbeek, Radboud University Nijmegen Medical Center Department of Human Genetics Nijmegen NetherlandsNicoline Hoogerbrugge, Radboud University Nijmegen Medical Center Department of Human Genetics Nijmegen NetherlandsJoannes H. J. M. van Krieken, Radboud University Nijmegen Medical Center Department of Pathology Nijmegen NetherlandsFokko M. Nagengast, Radboud University Nijmegen Medical C...

The first functional study of MLH3 mutations found in cancer patients

Genes, Chromosomes and Cancer — Mon, 02 Jun 2008 04:00:00 +0100

The MLH3 gene is one of the five mismatch repair (MMR) genes associated with hereditary nonpolyposis colorectal cancer (HNPCC). Eighteen different inherited MLH3 mutations have been reported as pathogenic in an international mutation database. In several cases, a mutation was found in a patient without a family history suggestive of inherited cancer susceptibility. In some cases, a similar mutation was also found in sporadic patients and/or healthy controls. Four patients carried an MLH3 mutation together with another inherited MMR gene variation. No functional analyses have been performed to assess the pathogenicity of these 18 mutations. MLH3 has been assumed to be less important in MMR than the other HNPCC susceptibility genes MSH2, MSH6, MLH1, and PMS2, and accordingly a low-risk gene ...

Cost-effectiveness analysis of prevention strategies for gynecologic cancers in Lynch syndrome

Cancer — Tue, 27 May 2008 04:00:00 +0100

In this study, the authors estimated the net health benefits and cost-effectiveness of these strategies in a Markov decision-analytic model.Five strategies were compared for a hypothetical cohort of women with Lynch syndrome: 1) no prevention ('reference'); 2) prophylactic surgery (hysterectomy and bilateral salpingo-oophorectomy) at age 30 years; 3) prophylactic surgery at age 40 years; 4) annual screening with endometrial biopsy, transvaginal ultrasound, and CA 125 from age 30 years; and 5) annual screening from age 30 years until prophylactic surgery at age 40 years (combined strategy). Net health benefit was measured in quality-adjusted life years (QALYs), and the primary outcome measured was the incremental cost-effectiveness ratio (ICER). Baseline and transition probabilities were ob...

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Uncertain pathogenicity of MSH2 variants N127S and G322D challenges their classification

International Journal of Cancer — Sat, 10 May 2008 04:00:00 +0100

We report the results of 3 different functional analyses characterizing the biochemical properties of these protein variants in vitro. We applied an immunoprecipitation assay to assess the MSH2-MSH6 interaction, a bandshift assay to study mismatch recognition and binding, and a MMR assay for repair efficiency. None of the experiments provided evidence on reduced functionality of these proteins as compared to wild-type MSH2. Our data demonstrate that MSH2 N127S and G322D per se are not sufficient to trigger MMR deficiency. This together with variable clinical phenotypes in the mutation carriers suggest no or only low cancer risk in vivo. © 2008 Wiley-Liss, Inc. (Source: International Journal of Cancer)

Malignant melanoma in patients with hereditary nonpolyposis colorectal cancer

British Journal of Dermatology — Fri, 02 May 2008 09:18:49 +0100

British Journal of Dermatology, Volume 0, Issue 0, Page ???, OnlineEarly Articles. SummaryBackground Malignant melanoma (MM) is the most aggressive skin cancer. Most MMs are sporadic, and in this setting an association with mismatch repair (MMR) gene mutations, typical of hereditary nonpolyposis colorectal cancer (HNPCC) tumours, has ... (Source: British Journal of Dermatology)

Lynch syndrome in women less than 50 years of age with endometrial cancer.

Obstetrics and Gynecology — Thu, 01 May 2008 04:00:00 +0100

CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III. PMID: 18448750 [PubMed - in process] (Source: Obstetrics and Gynecology)

A novel missense MSH2 gene mutation in a patient of a Korean family with hereditary nonpolyposis colorectal cancer.

Cancer Genetics and Cytogenetics — Tue, 15 Apr 2008 04:00:00 +0100

Authors: Park SJ, Lee KA, Park TS, Kim NK, Song J, Kim BY, Choi JR Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer-susceptible syndrome that predisposes to the early development of colorectal cancer. Germline mutations in DNA mismatch repair genes, particularly MLH1 and MSH2, are associated with the clinical phenotype of HNPCC. A previously unreported, novel missense mutation in exon 3 of the MSH2 gene (c.380A>T) was identified in the proband and a different missense mutation in exon 3 of MSH2 gene (c.505A>G) was noted in the mother, with a mutual splice mutation in intron 12 of the MSH2 gene in the proband, mother, and younger brother. Here, we report the clinical implications of a novel mutation in a patient with early-onset colorectal cancer a...