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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lynch syndrome (clinically referred to as HNPCC - Hereditary Non-Polyposis Colorectal Cancer) is a frequent, autosomal, dominantly-inherited cancer predisposition syndrome caused by various germline alterations that affect DNA mismatch repair genes, mainly MLH1 and MSH2. Patients inheriting this predisposition are susceptible to colorectal, endometrial and other extracolonic tumors. It has recently been shown that germline deletions of the last few exons of the EPCAM gene are involved in the etiology of Lynch syndrome. Such constitutional mutations lead to subsequent epigenetic silencing of a neighbouring gene, here, MSH2, causing Lynch syndrome. Thus, deletions of the last few exons of EPCAM constitute a distinct class of mutations associated with HNPCC. Worldwide, several investigators have reported families with EPCAM 3'end deletions. The risk of colorectal cancer in carriers of EPCAM deletions is comparable to situations when patients are MSH2 mutation carriers, and is associated with high expression levels of EPCAM in colorectal cancer stem cells. A lower risk of endometrial cancer was also reported. Until now the standard diagnostic tests for Lynch syndrome have contained analyses such as immunohistochemistry and tests for microsatellite instability of mismatch repair genes. The identification of EPCAM deletions or larger EPCAM-MSH2 deletions should be included in routine mutation screening, as this has implications for cancer predisposition.
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PMID:Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review. 2393 13

Large genomic rearrangements (LGRs) in DNA-mismatch-repair (MMR) genes, particularly among MSH2 gene, are frequently involved in the etiology of Lynch syndrome (LS). The Multiplex Ligation and Probe Amplification assay (MLPA) is commonly used to identify such alterations. However, in most cases, the MLPA-identified alteration is not characterized at the molecular level, which might be important to identify recurrent alterations and to analyze the molecular mechanisms underlying these mutational events. Probands from a cohort of Lynch Syndrome families were screened for point mutation in MMR genes, subsequently the MLPA assay was used for LGR screening. The identified MLPA alteration was confirmed by cDNA, CGH-microarrays or massive parallel sequencing. In this study, we have delimited the region of 11 LGRs variants on MSH2 locus. Six of them were fully characterized the breakpoints and 9 of them were considered pathogenic. According to our data, LGR on MSH2 locus constituted the 10.8% (9 out of 83) of pathogenic germline alterations found in LS. The frequency of colorectal cancer (CRC) and endometrial cancer (EC) in LGR carriers was 55% and 11% respectively. Analysis of the breakpoint sequences revealed that in 3 cases, deletions appeared to originate from Alu-mediated recombination events. In the remaining cases, sequence alignment failed to detect microhomology around the breakpoints. The present study provides knowledge on the molecular characterization of MSH2 LGRs, which may have important implications in LS diagnosis and Genetic Counseling. In addition, our data suggests that nonhomologous events would be more frequently involved in the etiology of MSH2 LGRs than expected.
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PMID:Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families. 2403 44

Lynch syndrome confers an increased risk to various types of cancer, in particular early onset colorectal and endometrial cancer. Mutations in mismatch repair (MMR) genes underlie Lynch syndrome, with the majority of mutations found in MLH1 and MSH2. Mutations in MSH6 have also been found but these do not always cause a clear cancer predisposition phenotype and MSH6-defective tumors often do not show the standard characteristics of MMR deficiency, such as microsatellite instability. In particular, the consequences of MSH6 missense mutations are challenging to predict, which further complicates genetic counseling. We have previously developed a method for functional characterization of MSH2 missense mutations of unknown significance. This method is based on endogenous gene modification in mouse embryonic stem cells using oligonucleotide-directed gene targeting, followed by a series of functional assays addressing the MMR functions. Here we have adapted this method for the characterization of MSH6 missense mutations. We recreated three MSH6 variants found in suspected Lynch syndrome families, MSH6-P1087R, MSH6-R1095H and MSH6-L1354Q, and found all three to behave like wild type MSH6. Thus, despite suspicion for pathogenicity from clinical observations, our approach indicates these variants are not disease causing. This has important implications for counseling of mutation carriers.
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PMID:Functional analysis in mouse embryonic stem cells reveals wild-type activity for three MSH6 variants found in suspected Lynch syndrome patients. 2404 Mar 39

Endometrial cancer is the first malignancy in 50% of women with Lynch syndrome, an autosomal dominant cancer-prone syndrome caused by germline mutations in genes encoding components of the DNA mismatch repair (MMR) pathway. These women (2-4% of all those with endometrial cancer) are at risk of metachronous colorectal cancer and other Lynch syndrome-associated cancers, and their first-degree relatives are at 50% risk of Lynch syndrome. Testing all women newly diagnosed with endometrial cancer for Lynch syndrome may have clinical utility for the index case and her relatives by alerting them to the benefits of surveillance and preventive options, primarily for colorectal cancer. The strategy involves offering germline DNA mutation testing to those whose tumour shows loss-of-function of MMR protein(s) when analysed for microsatellite instability (MSI) and/or by immunohistochemisty (IHC). In endometrial tumours from unselected patients, MSI and IHC have a sensitivity of 80-100% and specificity of 60-80% for detecting a mutation in an MMR gene, though the number of suitable studies for determining clinical validity is small. The clinical validity of strategies to exclude those with false-positive tumour test results due to somatic hypermethylation of the MLH1 gene promoter has not been determined. Options include direct methylation testing, and excluding those over the age of 60 who have no concerning family history or clinical features. The clinical utility of Lynch syndrome testing for the index case depends on her age and the MMR gene mutated: the net benefit is lower for those diagnosed at older ages and with less-penetrant MSH6 mutations. To date, women with these features are the majority of those diagnosed through screening unselected endometrial cancer patients but the number of studies is small. Similarly, clinical utility to relatives of the index case is higher if the family's mutation is in MLH1 or MSH2 than for MSH6 or PMS2. Gaps in current evidence include a need for large, prospective studies on unselected endometrial cancer patients, and for health-economic analysis based on appropriate assumptions.
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PMID:Genetic testing strategies in newly diagnosed endometrial cancer patients aimed at reducing morbidity or mortality from lynch syndrome in the index case or her relatives. 2405 92

The MSH6 gene is one of the mismatch repair genes involved in Lynch syndrome and its mutations account for 10-20% of Lynch syndrome. Although previous studies suggested that the difference of the geographical region affects the clinical phenotype of Lynch syndrome, there has been no report on the detailed features of Japanese Lynch syndrome patients carrying an MSH6 mutation. The aim of the present study was to investigate the clinical and molecular features of MSH6 mutation carriers in Japan. Surgically resected 1720 colorectal carcinoma specimens were screened by microsatellite instability (MSI) testing and the MSI-high cases were subjected to a germline mutation analysis of the mismatch repair genes MLH1, MSH2 and MSH6. We investigated the clinical and molecular features of the MSH6 variants, such as the family cancer history, pathological findings, immunohistochemistry, methylation status of the MLH1 promoter and BRAF mutation in the colorectal tumor. Furthermore, the impact of the missense variants on MSH6 protein was predicted by using in silico tools. We identified nine novel pathogenic mutations and eight unclassified missense variants. Among the eight missense variants, three were suspected pathogenic by in silico analysis. We also found that most colorectal cancers in the MSH6 mutation carrier were diagnosed after the age of 50 and were localized distally. Furthermore, the mean age at diagnosis of endometrial cancer in Japanese MSH6 mutation carriers (49.2 years) was earlier than previous reports from Western countries (56.5 years). These results may improve the surveillance program for Japanese MSH6 mutation carriers.
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PMID:Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patients. 2410 Aug 70

We have recently experienced an endometrial cancer 12 years after the diagnosis of colon cancer with Lynch syndrome. A 49-year-old Korean woman had a family history of colon cancer. Her mother had colon cancer at 56-year-old, and her brother had colon cancer at 48 years old. The patient received surgery for endometrial cancer at the same hospital 12 years after being treated for colon cancer. Immunohistochemistry showed that her endometrial tissue stained negative for MSH2. A microsatellite instability test was performed and showed the presence of instability high microsatellite instability. An hMLH2 gene mutation was detected at codon 629 codon of exon 12, in which a glutamine was replaced with an arginine (1886A>G [p.Gln629Arg]). To our knowledge, this is the first case of metachronous cancer in a Lynch syndrome family in Korea with a gap of more than ten years between cancer diagnoses.
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PMID:One case of endometrial cancer occurrence: Over 10 years after colon cancer in Lynch family. 2439 21

Although there is consensus on the cost-effectiveness of a universal approach of screening all colorectal cancer patients for Lynch syndrome (LS) using mismatch-repair (MMR) protein immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing, the question of universal versus selective screening of endometrial cancer patients remains to be resolved. We have prospectively implemented a selective screening algorithm for newly diagnosed endometrial cancer patients, triggered by patient age 50 years or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, and/or presence of MMR-associated tumor morphology. Four-protein MMR IHC and MSI testing were performed if any of the criteria were met. This algorithm excluded screening of older patients without a cancer pedigree and whose tumors lacked MMR morphology. The aim of this study was to retrospectively determine whether these exclusion criteria missed any tumors with abnormal MMR. Among 273 consecutive patients with newly diagnosed endometrial cancers, 181 (66%) lacked criteria for screening. Retrospective MMR IHC confirmed intact MMR in 177 (97.8%) of these 181 unscreened patients, loss of MSH6 in 1 patient (0.5%), and loss of MSH1/PMS2 due to MLH1 promoter hypermethylation in 3 patients (1.7%). In comparison, 41% of patients fulfilling 1 or more criteria for screening had abnormal MMR IHC/MSI, mostly consisting of loss of MLH1/PMS2. MMR morphology contributed to detection of 92% of the abnormal MMR cases while cancer pedigree contributed to detection of the remainder. All of the abnormalities due to MSH2 and PMS2 were detected by the screening algorithm, but 1 of the 4 MSH6 cases was not. The latter finding is consistent with the literature that MSH6 endometrial cancers exhibit a phenotype different than those of the other MMR genes. We conclude that a genotype-specific approach to screening endometrial cancer for LS could consist of universal testing by MSH6 IHC and selective testing by MLH1, PMS2, and MSH2 IHC on the basis of age, cancer pedigree, and MMR morphology. Cost-effectiveness of this hybrid selective strategy deserves further study, particularly in comparison with a universal strategy. Further work to identify phenotypic features of endometrial cancers with methylated MLH1 that would allow them to be excluded from LS screening would also contribute to cost-effectiveness.
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PMID:Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome. 2450 59

Lynch syndrome (LS) is an autosomal dominant inherited disease that is associated with an increased risk for colorectal and endometrial cancer due to germline mutations in mismatch-repair (MMR) genes. Whereas primary tumors in this syndrome are widely recognized, the relative risk(s) of secondary malignancies, particularly breast cancer, in LS patients are still poorly characterized. To provide an improved assessment of these risks, MMR status was evaluated in secondary tumors from a series of patients with index tumors of known MMR status (both proficient and deficient). A total of 1252 tumors (index tumors) and all secondary malignancies were tested for MMR by immunohistochemistry (MSH2, MSH6, MLH1, PMS2) between 1992 and 2013. Tumors with MLH1/PMS2 deficiency were tested for hypermethylation or BRAF mutation, when appropriate. Of the 1252 index tumors, 162 were MMR deficient (dMMR), and, of that subset, 32 secondary tumors were identified (19.7%). In contrast, 80 secondary tumors were identified in the proficient (intact) group (7.3%). Although secondary malignancies were more common in the dMMR group (P=0.0001), there was no trend in tumor type. Specifically, breast cancer was not overly represented in the dMMR group. When secondary tumors had dMMR, they were more likely to have deficiency in MSH2/MSH6 than in MLH1/PMS2 (P=0.01). Of the patients with tumors exhibiting dMMR, women were more likely to have a dMMR secondary tumor in this series (P=0.0001); however, breast cancer was not overly represented, and our study provides no evidence that it is more frequent in LS. MSH2/MSH6 deficiency is more commonly associated with a secondary tumor compared with MLH1/PMS2 deficiency, when methylation/BRAF status is taken into account.
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PMID:Risk of secondary malignancy (including breast) in patients with mismatch-repair protein deficiency. 2492 35

Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%-70% lifetime risk of colorectal cancer, 40%-60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In a subset of patients, Lynch syndrome is caused by 3' end deletions of the EPCAM gene, which can lead to epigenetic silencing of the closely linked MSH2. Relying solely on age and family history based criteria inaccurately identifies eligibility for Lynch syndrome screening or testing in 25%-70% of cases. There has been a steady increase in Lynch syndrome tumor screening programs since 2000 and institutions are rapidly adopting a universal screening approach to identify the patients that would benefit from genetic counseling and germline testing. These include microsatellite instability testing and/or immunohistochemical testing to identify tumor mismatch repair deficiencies. However, universal screening is not standard across institutions. Furthermore, variation exists regarding the optimum method for tracking and disclosing results. In this review, we summarize traditional screening criteria for Lynch syndrome, and discuss universal screening methods. International guidelines are necessary to standardize Lynch syndrome high-risk clinics.
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PMID:Lynch syndrome: an updated review. 2497 65

Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Mutation carriers are at substantially increased risk of developing cancers of the colorectum and endometrium, among others. Given recent recommendations for universal, cost-effective screening of all patients with newly diagnosed colorectal cancer using MMR protein immunohistochemistry, we evaluated MMR protein expression in a series of endometrial cancers in the general population. A total of 605 consecutive cases of primary endometrial cancer at a single institution (1997 to 2013) were evaluated regardless of age, family history, or histologic features. Evaluation methods consisted of immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2, followed by DNA methylation analysis for cases with MLH1/PMS2 deficiency. Germline mutation testing was performed on a subset of cases. Forty MMR-deficient, nonmethylated endometrial cancers were identified: 3 MLH1/PMS2 and 37 MSH6/MSH2 protein deficiencies. Only 25% occurred in women below 50 years of age (range, 39 to 88 y), 1 of which was in a risk-reducing hysterectomy specimen. Only 15% of patients had a prior history of carcinoma, including only 2 patients with prior colorectal carcinoma. Most (80%) of the endometrial cancers were purely endometrioid; there were 2 mixed endometrioid/mucinous, 1 mucinous, 1 serous, 2 clear cell, and 2 carcinosarcoma cases. When grading was applicable, 40% of the endometrial malignancies were FIGO grade 1, 34% grade 2, and 26% grade 3. Thirteen percent arose in the lower uterine segment, and 23% had tumor-infiltrating lymphocytes. Of the tumors with known germline testing, 41% with a LS-associated germline mutation were not associated with any of the traditional indicators that have been recommended for LS screening (ie, age 50 y or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, presence of MMR-associated tumor morphology, or location in the lower uterine segment). These data suggest that a significant number of LS-associated endometrial carcinomas are missed using clinical, histologic, and locational screening parameters and provide support for universal screening of all newly diagnosed endometrial cancers.
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PMID:Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer. 2522 68


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