Women with synchronous primary cancers of the endometrium and ovary: do they have Lynch syndrome?

PURPOSE: Lynch syndrome (hereditary nonpolyposis colorectal cancer; HNPCC) is an autosomal-dominant cancer predisposition syndrome that increases risk for multiple cancers, including colon, endometrial, and ovarian cancer. Revised Bethesda Criteria recommend that patients with two HNPCC-associated cancers undergo molecular evaluation to determine whether they have a mismatch repair (MMR) defect associated with HNPCC. The purpose of our study was to determine the likelihood of MMR defects (MSH2, MSH6, MLH1) in women with synchronous endometrial and ovarian cancer. PATIENTS AND METHODS: Between 1989 and 2004, 102 women with synchronous endometrial and ovarian cancers were identified; 59 patients had tumor blocks available for analysis. Patients were divided into risk groups based on family history: high (met Amsterdam criteria), medium (personal history or first-degree relative with an HNPCC-associated cancer), and low (all others). Protein expression for MSH2, MSH6, and MLH1 was evaluated by immunohistochemistry. Microsatellite instability and MLH1 promoter methylation analyses were performed on a subset of cases. RESULTS: Median age was 50 years. Two patients met Amsterdam criteria for HNPCC. Five additional patients, all medium-risk, had molecular findings consistent with a germline mutation of either MSH2 or MLH1. None of the low-risk patients had molecular results consistent with a germline mutation. CONCLUSION: Overall, 7% of women in our cohort met either clinical or molecular criteria for Lynch syndrome. All of these women had a prior history or a first-degree relative with an HNPCC-associated cancer. Limiting genetic evaluation to women with synchronous endometrial and ovarian cancer who have a family history suggestive of HNPCC may appropriately identify women with Lynch syndrome.     

Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients

Endometrial cancer is the most common cancer in women with Lynch syndrome. The identification of individuals with Lynch syndrome is desirable because they can benefit from increased cancer surveillance. The purpose of this study was to determine the feasibility and desirability of molecular screening for Lynch syndrome in all endometrial cancer patients. Unselected endometrial cancer patients (N = 543) were studied. All tumors underwent microsatellite instability (MSI) testing. Patients with MSI-positive tumors underwent testing for germ line mutations in MLH1, MSH2, MSH6, and PMS2. Of 543 tumors studied, 118 (21.7%) were MSI positive (98 of 118 MSI high and 20 of 118 MSI low). All 118 patients with MSI-positive tumors had mutation testing, and nine of them had deleterious germ line mutations (one MLH1, three MSH2, and five MSH6). In addition, one case with an MSI-negative tumor had abnormal MSH6 immunohistochemical staining and was subsequently found to have a mutation in MSH6. Immunohistochemical staining was consistent with the mutation result in all seven truncating mutation-positive cases but was not consistent in two of the three missense mutation cases. We conclude that in central Ohio, at least 1.8% (95% confidence interval, 0.9-3.5%) of newly diagnosed endometrial cancer patients had Lynch syndrome. Seven of the 10 Lynch syndrome patients did not meet any published criteria for hereditary nonpolyposis colorectal cancer, and six of them were diagnosed at age >50. Studying all endometrial cancer patients for Lynch syndrome using a combination of MSI and immunohistochemistry for molecular prescreening followed by gene sequencing and deletion analysis is feasible and may be desirable.     

Genetic testing by cancer site: colon (nonpolyposis syndromes)

ABSTRACT: Lynch syndrome, which is associated with mutations in 1 of 4 mismatch repair genes (MLH1, MSH2, MSH6, and PMS2), is a well-described hereditary cancer predisposition syndrome associated with a substantial risk of colon, rectum, and endometrial cancer. Historically, individuals with Lynch syndrome were identified using clinical classification criteria that have since been shown to be ineffective in most clinical settings, giving way to a more molecular diagnostic approach. These techniques have been repeatedly discussed in the literature, and there are multiple considerations in determining the best approach for a specific family. We review these approaches here as well as the clinical presentation of Lynch syndrome. Although still a relatively rare condition, we stress the importance of the identification of individuals with Lynch syndrome, given the clear data that predictive testing of at-risk family members and subsequent screening for cancers can reduce mortality associated with colorectal and endometrial cancer in these families.     

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

Familial colorectal cancer (CRC) accounts for 10–15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2–4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. 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.     

Gynecologic Cancers in Lynch Syndrome/HNPCC

Recent studies have estimated that the lifetime risk of endometrial cancer in women with Lynch syndrome/hereditary non-polyposis colorectal cancer syndrome (Lynch/HNPCC) is 40–60%. This risk equals or exceeds their risk for colon cancer. While much research has been done to define the natural history and molecular features of Lynch/HNPCC associated colon cancer, there has been considerably less research defining Lynch/HNPCC associated endometrial cancer. This article will review current information regarding the clinico-pathologic features of Lynch/HNPCC associated endometrial cancer. In addition, current consensus guidelines for endometrial cancer screening and prevention for women with Lynch/HNPCC will be discussed. Given the increased risk of multiple cancers, changing the name of this syndrome from hereditary non-polyposis colorectal cancer syndrome to Lynch Syndrome may benefit both patients and clinicians. Clinicians caring for women with Lynch/HNPCC may stress colon cancer screening and prevention without reviewing endometrial cancer risks and symptoms or screening and prevention options. Perhaps more importantly, women with Lynch/HNPCC may focus on colon cancer risks and lack understanding of endometrial cancer risks. With increasing evidence that women with Lynch/HNPCC have significant risks for both colon and endometrial cancers, we believe a multi-disciplinary approach to the management of these individuals is crucial.     

Risk of endometrial cancer for women diagnosed with HNPCC‐related colorectal carcinoma

The risk of endometrial cancer (EC) subsequent to a diagnosis of colorectal cancer in women with a germline mutation in a mismatch repair gene [Lynch syndrome or hereditary non‐polyposis colon cancer (HNPCC)] is unknown. We estimated the risk of EC following a diagnosis of colorectal carcinoma (CRC) for women with Lynch syndrome. A retrospective cohort study was performed on women diagnosed with CRC with a germline mutation in a mismatch repair (MMR) gene (Lynch syndrome cases), and women with microsatellite stable (MSS) CRC who were not known to carry a germline mutation (non‐Lynch cases), identified from the Colon Cancer Family Registry. The incidence of EC following CRC was estimated and compared for women with and without Lynch syndrome, using adjusted hazards ratios calculated for time at risk among each group. A total of 112 women with Lynch syndrome and a previous diagnosis of CRC were compared with 908 women without Lynch and with a MSS CRC diagnosis. The estimated 10‐year cumulative risk of EC subsequent to CRC was 23.4% [95% confidence interval (CI): 15–36%] for Lynch syndrome women compared with 1.6% (95% CI: 0.7–3.8%) for non‐Lynch women. After adjusting for ascertainment, age at diagnosis and diagnosis of other cancers, risk of subsequent diagnosis with EC was elevated sixfold in women with Lynch syndrome compared with non‐Lynch women (HR 6.2; 95% CI 2.2–17.3; p = 0.001). Approximately one quarter of women diagnosed with Lynch syndrome‐associated CRC developed EC within 10 years. This supports the sentinel cancer concept and suggests that active and early management is important for these women.     

Genetic counseling and cascade genetic testing in Lynch syndrome

Lynch syndrome is the most common cause of inherited colorectal and endometrial cancers. Individuals with Lynch syndrome have a 10–80 % lifetime risk for colorectal cancer and a 15–60 % lifetime risk for endometrial cancer. Both cancers are preventable through chemoprevention, intensive cancer surveillance, and risk-reducing surgery options. Efforts to identify as many individuals with Lynch syndrome as possible will prevent cancers and save lives. This includes the traditional cancer genetic counseling model whereby individuals with and without cancer are evaluated for a possible Lynch syndrome diagnosis based on their personal and family history of colon polyps and cancers. It also includes universal tumor screening for Lynch syndrome whereby all individuals with colorectal or endometrial cancer are screened for tumor features of Lynch syndrome at the time of diagnosis. Those with tumors suspicious for Lynch syndrome are referred for cancer genetic counseling regardless of their family history of cancer. This two approaches must be maximized to attain high patient reach. Finally, and perhaps most importantly, cascade testing among the at-risk relatives of those diagnosed with Lynch syndrome is critically important to maximize the diagnosis of individuals with Lynch syndrome. In fact, the cost-effectiveness of universal tumor screening for Lynch syndrome relies entirely on counseling and testing as many at-risk individuals as possible since young unaffected individuals stand to benefit the most from an early diagnosis of Lynch syndrome. This approach must be optimized to achieve high family reach. It will take a concerted effort from patients, clinicians and public health officials to improve current approaches to the diagnosis of Lynch syndrome and the prevention and treatment of Lynch syndrome-associated cancer but these lessons can be applied to other conditions as the ultimate example of personalized medicine.     

Synchronous gynecologic malignancy and preliminary results of Lynch syndrome

Objective

Lynch syndrome is a hereditary cancer syndrome that increases the risks of colorectal and gynecologic malignancies such as endometrial and ovarian cancer. Studies have shown that mutations in mismatch repair genes (MSH2, MSH6, and MLH1) are associated with Lynch syndrome. The aim of our study was to estimate the value of MSH2, MSH6, and MLH1 immunohistochemistry based on family history in a Korean sample.

Methods

Thirty six women with synchronous gynecologic tumors of endometrial and ovarian cancer were identified among patients being treated at our institution. Among them, 32 patients had tumor blocks (total 62 slides) available for analysis. According to a diagnostic algorithm, we performed immunohistochemistry analyses. Staining was scored based on intensity and proportion (negative or 0: intensity undetectable or minimal, proportion <5%; weak or 1+: intensity mild, proportion 5-30%; strong or 2+: intensity moderate to marked, proportion 30-99%).

Results

Among 32 eligible patients, 9 (28%) had a family history of cancer. Six patients (19%) were negative for MLH1; among them, four (4/6) were negative at both sites. Nine patients (28%) were negative for MSH2 or MSH6 at both sites or negative for both MSH2 and MSH6. Among these three patients showed negative staining for both sites. The three patients showing negative staining for MLH1, MSH2, and MSH6 at both sites with family history were considered to be the screening positive groups of Lynch syndrome.

Conclusion

In this study, the frequency of Lynch syndrome associated immunohistochemical staining (MLH1, MSH2, and MSH6) group was estimated as 9% (3/32) among Korean women with synchronous gynecologic tumors.     

Hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, is the most common form of hereditary colorectal cancer (CRC). A well-orchestrated cancer family history is essential for its diagnosis since, unlike its familial adenomatous polyposis (FAP) hereditary cancer counterpart, HNPCC lacks distinguishing clinical stigmata of its cancer genetic risk. Discoveries in the 1990s of germ-line mutations, the most common of which are hMSH2 and hMLH1, have added enormous power to the diagnosis of Lynch syndrome. Its medical management is contingent upon its natural history. For example, approximately 70% of CRCs occur proximal to the splenic flexure, with one-third of the cancers occurring in the cecum, thereby mandating full colonoscopy. A high rate of metachronous CRCs indicates the need for no less than a subtotal colectomy for the management of initial CRC. Genetic counseling is essential prior to DNA testing, and at the time of disclosure of the results. Education of patients as well as physicians about all facets of this disorder is extremely important. If patients are to show compliance with germ-line testing, screening, and management options, they must understand the natural history and the significance of their genetic risk status. Physicians must also be aware of clinical nuances of this disorder to provide the necessary care.     

Screening for Lynch syndrome in young Saudi colorectal cancer patients using microsatellite instability testing and next generation sequencing

Individuals with Lynch syndrome (LS) have germline variants in DNA mismatch repair (MMR) genes that confer a greatly increased risk of colorectal cancer (CRC), often at a young age. Identification of these individuals has been shown to increase their survival through improved surveillance. We previously identified 33 high risk cases for LS in the Saudi population by screening for microsatellite instability (MSI) in the tumor DNA of 284 young CRC patients. The aim of the present study was to identify MMR gene variants in this cohort of patients. Peripheral blood DNA was obtained from 13 individuals who were at high risk of LS due to positive MSI status and young age (<60 years at diagnosis). Next generation sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification were used to screen for germline variants in the MLH1, MSH2, MSH6 and PMS2 MMR genes. These were cross-referenced against several variant databases, including the International Society for Gastrointestinal Hereditary Tumors Incorporated database. Variants with pathogenic or likely pathogenic significance were identified in 8 of the 13 high risk cases (62%), comprising 4 in MLH1 and 4 in MSH2. All carriers had a positive family history for CRC or endometrial cancer. Next generation sequencing is an effective strategy for identifying young CRC patients who are at high risk of LS because of positive MSI status. We estimate that 7% of CRC patients aged <60 years in Saudi Arabia are due to LS, potentially involving around 50 new cases per year.     

Interpretation of genetic testing for lynch syndrome in patients with putative familial colorectal cancer

Colorectal cancer (CRC) risk assessment involves the evaluation of an individual's personal and family history for characteristics of an inherited susceptibility to develop CRC. Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common cause of hereditary CRC, underlying 2% to 3% of patients with newly diagnosed (incident) CRC. Risk assessment for LS is complex, and the interpretation of the many available tests can be challenging even for the genetics specialist. A move toward universal (reflex) LS screening for mismatch repair in all patients with incident CRC supports the importance of improving the awareness and understanding of LS testing, teaching rational testing approaches, and honing interpretive skills among cancer care providers. This article reviews important clinical features of LS genetic evaluation using 3 pedigree-based case examples from the Fox Chase Cancer Center Gastrointestinal Risk Assessment Clinic.     

Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (hnpcc) syndrome

Identification of hereditary non-polyposis colorectal cancer (HNPCC) indicates theoretical life-time risks of 50% for the descendants of an affected family member and of 100% for the true gene carriers. However, besides colorectal cancer (CRC), many other cancer types and sites are also involved, which gives reason to evaluate the magnitude of risk for various other cancer types. A detailed pedigree analysis of 40 families with HNPCC identified 414 patients affected with cancer. A Kaplan-Meier life-table analysis for the cumulative risk of various cancers was performed on the basis of the 293 putative gene carriers who had adequate clinical and histological documentation of their tumors. Cumulative risks were highest for colorectal (78%) and endometrial cancers (43%, women only), followed by gastric, biliary tract, urinary tract and ovarian cancers (19-9%). For the other probably HNPCC-related cancer types, such as small bowel carcinoma and brain tumors, the life-time risk was only 1%. The risk of any metachronous cancer reached 90% after treatment of CRC and 75% after endometrial cancer; the second tumor was most often a new CRC or endometrial cancer. CRC remains the most important cancer type in the HNPCC syndrome but does not develop in all gene carriers. This makes the decision of possible prophylactic colectomy for test-detected gene carriers difficult. Of the many other cancer types involved, at least endometrial cancer is common enough to necessitate a specific surveillance program. © 1995 Wiley-Liss, Inc.     

Analysis of Hereditary Nonpolyposis Colorectal Cancer in Malay Cohorts using Immunohistochemical Screening

Background: Lynch syndrome (LS) is an inherited predisposition to colorectal, endometrial (uterine) andother cancers. Although most cancers are not inherited, about 5 percent (%) of people who have colorectal orendometrial cancer have the Lynch syndrome. It involves the alteration of mismatch repair (MMR) genes; MLH1,MSH2, MSH6 or PMS2. In this study, we analyzed the expression of MMR proteins in colorectal cancer in a Malaycohort by immunohistochemistry. Materials and Methods: A total of 17 patients were selected fulfilling one of theBethesda criteria: colorectal cancer diagnosed in a patient aged less than 50 years old, having synchronous andmetachronous colorectal cancer or with a strong family history. Immunohistochemical staining was performedon paraffin embedded tumour tissue samples using four antibodies: MLH1, MSH2, MSH6 and PMS2. Results:Twelve out of 17 patients (70.6%) were noted to have a family history. A total of 41% (n=7) of the patients hadabnormal immunohistochemical staining with one or more of the four antibodies. Loss of expression were notedin 13 tumour tissues with a negative staining score <4. Of 13 tumour tissues, four showed loss expression ofMLH1. For PMS2, loss of expression were noted in five cases. Both MSH2 and MSH6 showed loss of expressionin two tumour tissues respectively. Conclusions: Revised Bethesda criteria and immunohistochemical analysisconstituted a convenient approach and is recommended to be a first-line screening for Lynch syndrome in Malaycohorts.     

HNPCC (Lynch Syndrome): Differential Diagnosis,Molecular Genetics and Management - a Review

HNPCC (Lynch syndrome) is the most common form of hereditary colorectal cancer (CRC), wherein it accounts for between 2-7 percent of the total CRC burden. When considering the large number of extracolonic cancers integral to the syndrome, namely carcinoma of the endometrium, ovary, stomach, hepatobiliary system, pancreas, small bowel, brain tumors, and upper uroepithelial tract, these estimates of its frequency are likely to be conservative. The diagnosis is based upon its natural history in concert with a comprehensive cancer family history inclusive of all anatomic sites. In order for surveillance and management to be effective and, indeed, lifesaving, among these high-risk patients, the linchpin to cancer control would be the physician, who must be knowledgeable about hereditary cancer syndromes, their molecular and medical genetics, genetic counseling, and, most importantly, the natural history of the disorders, so that the entirety of this knowledge can be melded to highly-targeted management.     

Lynch syndrome: implications for the surgeon

Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, is an autosomal dominant syndrome characterized by onset of colorectal cancer (CRC) at an early age, right-sided predominance, excess synchronous and metachronous colorectal neoplasms, and extracolonic neoplasms. It is the most common of the hereditary CRCs, so the practicing surgeon should expect to encounter patients with this disease. The diagnosis of HNPCC, which begins with a complete family history and a high index of suspicion by the clinician, has important implications in the management and surveillance of not only the affected individual but also for the individual's family. In this article, the diagnosis and management of Lynch syndrome will be reviewed, with emphasis on the implications for the surgeon.     

Screening and prevention of hereditary gynecologic cancers

Endometrial and ovarian cancer are the fourth and fifth most common malignancies in women, with approximately 40,000 new endometrial and 25,000 new ovarian cancers expected to be diagnosed in the Unites States this year. While the majority of these cancers will occur in the absence of a family history, approximately 5% of endometrial cancers and 10% of ovarian cancers will be the result of inherited defects in high-penetrance cancer susceptibility genes. With the identification and subsequent availability of clinical genetic testing for mutations in the genes associated with hereditary breast-ovarian cancer and the Lynch/hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, targeted risk-reduction using intensive screening, chemoprevention, and prophylactic surgery has become possible for women at inherited risk of gynecologic malignancies. We review the options for gynecologic cancer risk reduction in women with an inherited mutation in BRCA1, BRCA2, or one of the mismatch repair (MMR) genes associated with Lynch/HNPCC syndrome. Additionally, we outline ongoing questions and areas for future research.     

Clinical significance of tumor microsatellite instability and immunohistochemistry for mismatch repair deficiency in colorectal cancers

Referrals to genetics services are becoming increasingly common for patients who are diagnosed with early-onset colorectal cancer (CRC) or patients who have a family history of CRC. Microsatellite instability (MSI) testing and immunohistochemical analysis (IHC) of the patient’s tumor tissue, which assess indirectly the cellular status of DNA mismatch repair, have proven important tools for geneticists and genetic counselors to determine whether or not these individuals may be at risk for an inherited cancer syndrome, Lynch syndrome (a subset of hereditary nonpolyposis colorectal cancer). The application of tumor MSI/ IHC also extends to the group of providers involved in the diagnosis and management of CRC, demonstrating the growing clinical applicability of MSI/IHC testing. This review discusses the clinical utility of MSI/IHC analysis, including its benefits and limitations, and addresses some of the current debates surrounding testing.     

MLH1基因突变在Lynch综合征中的研究进展

结直肠癌是常见的消化系统恶性肿瘤,有些类型具有家族聚集性。Lynch综合征作为最常见的遗传性结直肠癌综合征,主要因相关基因突变致错配修复蛋白表达异常、减少或缺失而致病,其主要包括MLH1、MSH2、MSH6和PMS2基因。考虑到MLH1和MSH2基因的胚系突变占Lynch综合征总突变近90%,因此本文将着重综述近年来错配修复蛋白基因MLH1的突变,整理在不同国家和地区的重要创始人突变。通过对公共数据库已有报道突变及单中心收录数据比较,从而对其诊断,基因筛查,为了解不同人种和地域的Lynch综合征创始人突变提供一定的指导意义。     

Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: probability of synergistic effects

Mutations in the MLH1 and MSH2 genes account for a majority of cases of families with Lynch Syndrome. Germ-line mutations in MSH6, PMS2 and MLH3 are responsible for disease in a minority of cases, usually associated with milder and variable phenotypes. No germ-line mutations in MSH3 have so far been associated with Lynch Syndrome, although it is known that impaired MSH3 activity leads to a partial defect in mismatch repair (MMR), with low levels of microsatellite instability at the loci with dinucleotide repeats in colorectal cancer (CRC), thus suggesting a role for MSH3 in carcinogenesis. To determine a possible role of MSH3 as predisposing to CRC in Lynch syndrome, we screened MSH3 for germ-line mutations in 79 unrelated Lynch patients who were negative for pathogenetic mutations in MLH1, MSH2 and MSH6. We found 13 mutant alleles, including silent, missense and intronic variants. These variants were identified through denaturing high performance liquid chromatography and subsequent DNA sequencing. In one Lynch family, the index case with early-onset colon cancer was a carrier of a polymorphism in the MSH2 gene and two variants in the MSH3 gene. These variants were associated with the disease in the family, thus suggesting the involvement of MSH3 in colon tumour progression. We hypothesise a model in which variants of the MSH3 gene behave as low-risk alleles that contribute to the risk of colon cancer in Lynch families, mostly with other low-risk alleles of MMR genes.     

Clinical and histomolecular endometrial tumor characterization of patients at-risk for Lynch syndrome in South of Brazil

Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. Clinically, Lynch syndrome is characterized by early onset (45 years) of colorectal cancer (CRC), as well as extra-colonic cancer. Male and female carriers of Lynch syndrome-associated mutations have different lifetime risks for CRC and in women endometrial cancer (EC) may be the most common tumor. Whenever Amsterdam criteria are not fulfilled, the currently recommended laboratory screening strategies involve microsatellite instability testing and immunohistochemistry staining of the tumor for the major MMR proteins. The aim of this study was to estimate the frequency of MMR deficiencies in women diagnosed with EC who are at-risk for Lynch syndrome. Thirty women diagnosed with EC under the age of 50 years and/or women with EC and a first degree relative diagnosed with a Lynch syndrome-associated tumor were included. To assess MMR deficiencies four methods were used: multiplex PCR, Single Strand Conformation Polymorphism, Immunohistochemistry and Methylation Specific–Multiplex Ligation-dependent Probe Amplification. Twelve (40%) patients with EC fulfilling one of the inclusion criteria had results indicative of MMR deficiency. The identification of 5 women with clear evidence of MMR deficiency and absence of either Amsterdam or Bethesda criteria among 10 diagnosed with EC under the age of 50 years reinforces previous suggestions by some authors that these women should be considered at risk and always screened for Lynch syndrome after informed consent.