Lynch Syndrome-associated Endometrial Cancer Research Articles

Abstract IA013: Unique metabolic changes in Lynch syndrome-associated endometrial cancer

Abstract Lynch syndrome-associated endometrial cancers (ECs) are defined by germline mutations in DNA mismatch repair genes, including MSH2, MSH6, PMS2, and MLH1. Lynch syndrome (LS) tumors have received increased attention in the therapeutic context as these tumors are microsatellite instable and often reflect increased immune cell infiltration and enhanced response to immunotherapy. However, relatively little attention has been paid to pathogenesis of LS ECs. Women with LS represent an at-risk population who could benefit from cancer interception strategies due to a 60% cumulative lifetime risk of developing EC. We developed a mouse model of MSH2 loss targeted to the uterus to evaluate EC pathogenesis, with the goal of elucidating mechanisms that alter disease penetrance for women with hereditary risk for EC development. Our Progesterone Receptor-Cre Msh2f lox/flox mice (abbreviated Msh2KO) develop ECs that closely mimic human EC. Whole transcriptome profiling of Msh2KO EC and Msh2KO normal endometrium compared to wild-type endometrium identified “Mitochondrial dysfunction” as a significantly altered pathway in Msh2 deficiency, prompting our in-depth evaluation of mitochondrial alterations in Msh2KO mice, MSH2-deficient cell lines, and LS-associated EC patient specimens. We will discuss the impact of MSH2 deficiency across multiple measures of mitochondrial content, integrity, function, and metabolomic analyses in ECs using preclinical models and human tissue studies. Overall, our studies reveal that MSH2-deficient EC is characterized by mitochondrial DNA damage, mitochondrial content reduction, and decreased mitochondrial function. In addition, decreased mitochondrial respiration for energy production facilitates metabolic reprogramming toward glycolysis. We are conducting further studies to define mechanisms underlying mitochondrial defects due to MSH2 loss and opportunities for intervention. Mitochondrial and metabolic aberrations could serve as novel biomarkers for EC development and targets for cancer prevention in women with LS. Citation Format: Melinda S. Yates. Unique metabolic changes in Lynch syndrome-associated endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA013.

Lynch Syndrome-Associated Endometrial Cancer With Combined EPCAM-MSH2 Deletion: A Case Report.

BackgroundLynch syndrome (LS), an autosomal dominant disorder, is characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes like MSH2. EPCAM deletions cause a minority (3%) of LS cases. However, there are only a few reports of LS-associated endometrial cancer (LS-EC) induced by the inactivation of the MSH2 gene due to EPCAM deletions.Case PresentationWe present the case of a 45-years old woman diagnosed with endometrial cancer (EC). Definitive surgery revealed meso-differentiated endometrioid adenocarcinoma, stage IA without lymph-vascular space invasion. Four months later, she received radiation therapy (125I radioactive seeds implantation), and platinum-containing regimen combined chemotherapy because of vaginal stump metastasis of EC. After five years, we performed immunohistochemistry (IHC) on pelvic mass because of presacral metastatic lymph node. IHC showed the absence of MSH2 and MSH6 protein expression in the pelvic mass tissue. Peripheral blood was used for genetic testing based on her cancer diagnosis and family history of cancer in close relatives. Genetic testing revealed deletions of exon 8 and 9 in EPCAM and deletions of exon 1 and 8 in MSH2; thus, we diagnosed the presence of LS. The patient underwent interstitial brachytherapy (BT) of the presacral metastatic lymph node.ConclusionThis case highlights that patients with LS-EC who are carriers of combined EPCAM-MSH2 deletion might experience better oncologic outcomes even with early recurrence.

Distinct clinical and genetic mutation characteristics in sporadic and Lynch syndrome-associated endometrial cancer in a Chinese population

BackgroundThe diagnosis of Lynch syndrome-associated endometrial cancer patients is significant for early warning of their relatives. The purpose of this study was to provide diagnostic indicators of Lynch syndrome-associated endometrial cancer by screening the differential clinical and genetic characteristics. MethodsClinical information and hysterectomy specimens were collected from 377 eligible patients with endometrial cancer. The MLH1 methylation level was detected by an EZ DNA Methylation-Gold Kit. According to the above experimental results, the patients were then divided into sporadic endometrial cancer and suspected Lynch syndrome-associated endometrial cancer groups. A total of 62 samples were randomly selected for whole-exome sequencing. IBM SPSS Statistics 21 was used to compare the clinical data between the sporadic and suspected Lynch syndrome-associated endometrial cancer groups, and the relationship between the specific high-frequency-mutation genes and the clinical data. ResultsAccording to the results of MMR immunohistochemistry and MLH1 methylation, the sporadic endometrial cancer group included 361 patients and the suspected Lynch syndrome-associated endometrial cancer group included 16 patients in this study. In the clinical analysis, the average age of the suspected Lynch syndrome-associated endometrial cancer patients was 45.50 ± 11.50 years, which was significantly younger than the 51.17 ± 10.03 years of the sporadic endometrial cancer patients (P = 0.028). The average BMI of the suspected Lynch syndrome-associated endometrial cancer patients was 23.43 kg/m2 (CI: 20, 30), which was lower than the 26.50 kg/m2 of the sporadic endometrial cancer patients (P = 0.028). Combined with the WES data, MASP2, NADK and RNF223 were identified as three specific mutation sites related to age, FIGO stage and histology. ConclusionsCompared with the suspected endometrial cancer patients, the Lynch syndrome-associated endometrial cancer patients were younger and less obese. Mutations in MASP2, NADK and RNF223 might be regarded as genetic endometrial cancer features related to clinical characteristics.

Practice patterns for Lynch syndrome-associated endometrial cancer management in Korea

Practice patterns for Lynch syndrome-associated endometrial cancer management in Korea

Frequent loss of mutation-specific mismatch repair protein expression in nonneoplastic endometrium of Lynch syndrome patients.

Lynch syndrome is most often caused by a germline mutation in one of four DNA mismatch repair (MMR) genes (MLH1, PMS2, MSH2, or MSH6) or EPCAM and is associated with a significantly increased risk of endometrial cancer in affected women. Although universal screening of endometrial cancer for Lynch syndrome is becoming increasingly common by various algorithms using MMR immunohistochemistry and/or microsatellite instability testing by PCR, establishing the diagnosis of Lynch syndrome can be still challenging. MMR-deficient nonneoplastic colonic crypts have been recently described in Lynch syndrome patients with colorectal carcinoma, and have been proposed to be a novel indicator of Lynch syndrome. Presence of MMR-deficient nonneoplastic endometrial glands have not yet been systematically evaluated in Lynch syndrome patients. We performed MMR protein immunohistochemistry in prophylactic hysterectomies and endometrial curettings/biopsies from 27 patients with known Lynch syndrome confirmed by germline mutation analysis. A total of 56 control benign endometrial tissues were also analyzed, and included benign endometrium adjacent to MMR-deficient sporadic (MLH1 promoter hypermethylated) endometrial carcinoma (n = 9), adjacent to MMR-intact sporadic endometrial carcinoma (n = 27), and normal endometrium from hysterectomies performed for benign disease (n = 20). MMR protein deficient nonneoplastic endometrial glands were identified in 70% (19 of 27) of Lynch syndrome patients. In all 19 cases the MMR protein loss was specific for the patients' known germline mutation. None of the control cases showed loss of MMR protein expression in nonneoplastic endometrium. Our findings suggest that MMR-deficient nonneoplastic endometrial glands may be a unique, specific marker of Lynch syndrome, and may provide an important insight into the pathogenesis of Lynch syndrome-associated endometrial cancer. Evaluation of MMR protein expression of benign background endometrium in endometrial cancer patients may be further explored as a possible useful addition to the Lynch syndrome screening algorithm.

Comparison of screening strategies for Lynch syndrome in patients with newly diagnosed endometrial cancer: a prospective cohort study in China

BackgroundThe prevalence of Lynch syndrome and screening strategies for this disorder in Chinese patients with endometrial cancer have seldom been investigated. Such data would be essential for the screening, prevention, genetic counseling, and treatment of Lynch syndrome. The purpose of this prospective study was to determine the accuracy of the mismatch repair (MMR) protein immunohistochemistry (IHC), microsatellite instability (MSI) test, and clinical diagnostic criteria in screening for Lynch syndrome-associated endometrial cancer (LS-EC) in a prospective Chinese cohort.MethodsAll patients with newly diagnosed endometrial cancer (EC) were evaluated using clinical diagnostic criteria (Amsterdam II criteria and the revised Bethesda guidelines), MSI test, and IHC of MMR proteins in tumor tissues. For all patients, the screening results were compared with results of germline sequencing for pathogenic variants of MMR genes.ResultsBetween December 2017 and August 2018, a total of 111 unselected patients with newly diagnosed EC were enrolled. Six patients (5.4%) harbored a pathogenic germline mutation of MMR genes: 1 had a mutation in MutL homolog 1 (MLH1), 2 in MutS homolog 2 (MSH2), and 3 in MutS homolog 6 (MSH6). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for identifying LS-EC were 33.3%, 88.6%, 14.3%, and 95.9%, for the clinical criteria, 66.7%, 75.0%, 14.3%, and 97.3% for IHC of MMR proteins, 100%, 89.9%, 33.3%, and 100% for MSI test, and 100%, 72.4%, 20.0% and 100% for combined IHC and MSI test, respectively. The combination of IHC and MSI test had higher sensitivity and PPV than the clinical criteria (p = 0.030). MSI test and IHC were highly concordant for LS-EC screening (73/77, 94.8%).ConclusionThe accuracy of the combination of IHC of MMR proteins and MSI test for screening LS among Chinese patients with EC was superior to that of the clinical criteria.Trial registration NCT03291106. Registered on September 25, 2017

Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review

BackgroundLynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer.Case presentationHere we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome.ConclusionsBoth MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

Importance of PCR-based Tumor Testing in the Evaluation of Lynch Syndrome-associated Endometrial Cancer.

Lynch syndrome (LS) is a hereditary cancer syndrome caused by a germline mutation in a DNA mismatch repair gene, usually MLH1, MSH2, MSH6, or PMS2. The most common cancers associated with LS are colorectal adenocarcinoma and endometrial carcinoma. Identification of women with LS-associated endometrial cancer is important, as these women and their affected siblings and children are at-risk of developing these same cancers. Germline testing of all endometrial cancer patients is not cost effective, and screening using young age of cancer diagnosis and/or presence of family history of syndrome-associated is underutilized and ineffective. Therefore, most groups now advocate for tumor tissue testing to screen for LS, with germline testing targeted to women with abnormal tissue testing results. Immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 is used in many clinical laboratories for this tumor screening step, as immunohistochemistry is relatively inexpensive and is technically more accessible for smaller clinical labs. PCR-based tissue testing, whereas technically more challenging, does play an important role in the identification of these patients. MLH1 methylation analysis identifies women with tumor MLH1 loss who likely have sporadic endometrial cancer and do not need heightened cancer prevention surveillance. High levels of microsatellite instability have been identified in tumors with retained positive expression of mismatch repair proteins. Somatic sequencing of mismatch repair genes from tumor DNA, whereas not currently available in most clinical laboratories, is helpful in resolution of cases in which germline sequencing fails to identify a mutation in a mismatch repair gene. The tumor tissue testing approach can help to identify most women at-risk for germline mutations in a LS gene, but not all patients will be captured using this approach. Clinical suspicion can still play a pivotal role in accurately identifying a subset of these patients.

Comparison of lifestyle, hormonal and medical factors in women with sporadic and Lynch syndrome-associated endometrial cancer: A retrospective case-case study.

Data available on lifestyle-associated hormonal and medical factors among endometrial cancer (EC)-affected women who carry the Lynch Syndrome (LS) mutation is limited. The aim of the present retrospective case study was to compare the reproductive and medical history, as well as lifestyle-associated factors, among patients with LS and sporadic EC. The study population consisted of 50 verified germline mismatch repair (MMR) gene mutation carriers diagnosed with EC, and 110 sporadic EC patients. Data were collected using postal questionnaires. Apart from the mean age at the time of the EC diagnosis (LS, 48.7 years compared with sporadic patients, 55.2 years; P<0.0001), the characteristics of sporadic and LS EC patients were similar with regard to body mass index (BMI) at age 18, 40 or at the time of the survey, and smoking and alcohol consumption. LS women reported a significantly lower rate of spontaneous abortion (P=0.043) and also more frequent use of contraceptives (P=0.004). The prevalence of co-morbidities, including diabetes, atherosclerosis, hypercholesterolemia and hypertension, was similar between the LS and the sporadic groups. A trend for a higher prevalence of endometriosis among mutation carriers was detected (16.0 vs. 8.1%, P=0.137). As anticipated, the prevalence of gastrointestinal tract, urinary tract and ovarian cancer was higher among the LS women (P<0.0001, P=0.006 and P=0.056, respectively). Co-morbidity and lifestyle-associated factors appeared to be comparable among patients with LS and sporadic EC. The reported difference in the use of contraceptives warrants further investigation. Future studies are also required to address the possible association between LS and endometriosis.

Evaluation of DNA Mismatch Repair Protein Expression as a Preliminary Screening for Lynch Syndrome in Young Japanese Women with Endometrial Cancer

Background: Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant cancer syndrome. There is an urgent need to identify patients with Lynch syndrome among patients with endometrial cancer. We aimed to evaluate the efficacy of measuring DNA mismatch repair (MMR) expression in young Japanese endometrial cancer patients to differentiate sporadic and Lynch syndrome-associated tumors. Methods: In a retrospective analysis of 50-year-old or younger endometrial cancer patients, 106 tumors were evaluated for MSH2, MSH6, PMS2, and MLH1 expression by immunohistochemistry. Samples lacking MLH1 were further examined by real-time PCR to evaluate hypermethylation of the MLH1 promoter. Clinical characteristics of patients with suspected Lynch syndrome were then evaluated. Results: Among the 106 samples, 25 (23.6%) had reduced MMR protein expression; MLH1, MSH2 and MSH6 staining was negative in 14, 6 and 5 cases, respectively, while no samples were negative for PMS2. Among the 14 cases lacking MLH1 staining, 10 were found to be associated with MLH1 promoter hypermethylation. Therefore, 15 (14.2%) cases of suspected Lynch syndrome-associated endometrial cancer were found. These patients presented with a significantly lower body mass index and had more first-degree relatives diagnosed with a Lynch syndromeassociated cancer. Our cohort included three Lynch syndrome patients with known mutations, and tumor samples from these patients showed an absence of the specific MMR protein that was mutated. Conclusions: Our results demonstrate that immunohistochemical analysis of tumor samples for MMR protein expression can identify patients with Lynch syndrome. With early detection, colorectal cancer outcomes might be drastically improved.

Recent advances and future development on Lynch syndrome-associated endometrial cancer

Lynch综合征(Lynch syndrome,LS)又称作遗传性非息肉状结直肠癌(hereditary non-polyposis colorectal cancer,HNPCC),属常染色体显性遗传性疾病,由DNA错配修复(mismatch repair,MMR)基因突变引起,发病率占结直肠癌的2％ ～ 5％ [1-2].前期的研究多集中在LS相关结直肠癌,在基因水平和预防性研究中取得了较大进展.近年来,越来越多的证据显示在LS妇女中,发生子宫内膜癌的风险为40％ ～ 60％,达到甚至超过结直肠癌(49％),已作为首发肿瘤受到临床重视[3].以往临床医师先从年龄和家族史开始筛查,对怀疑的病例直接进行基因检测,但这样做是针对基因位点的特异性检测,会产生高昂的医疗费用。

Outcomes of screening endometrial cancer patients for Lynch syndrome by patient-administered checklist

ObjectiveThe aims of this study were to implement a patient-administered checklist designed to identify endometrial cancer patients at elevated risk for Lynch syndrome; measure subsequent genetic counseling and testing; and identify differences between those who attended genetic counseling and those who did not. MethodsWe developed a 4-item yes/no checklist of personal and family history risk factors for Lynch syndrome-associated endometrial cancer and recommended referral for genetic counseling for patients meeting any of the criteria. Retrospective chart review was performed to determine subsequent genetic counseling and testing outcomes over a 15month period. Results6/387 (1.6%) of endometrial cancer patients tested positive for a Lynch syndrome mutation. 4/24 (17%) of endometrial cancer patients who met referral criteria and attended genetic counseling tested positive. 38/70 (55%) of patients who met referral criteria were not seen for genetic counseling. Patients who were diagnosed with endometrial cancer at younger ages, who had primary surgery at our institution, or who met more than one referral criteria were more likely to be seen for genetic counseling. ConclusionsEndometrial cancer patients who met referral criteria and attended genetic counseling comprised a population enriched for Lynch syndrome. This approach allowed Lynch syndrome evaluation resources to be targeted to a population of patients that is high risk and interested in the information. The referral rate of at-risk patients needs to be improved, and allocating resources towards this goal could increase the identification of Lynch syndrome while avoiding some of the pitfalls of universal screening.

Chemoprevention of Endometrial Cancer in Lynch Syndrome: A Step Forward

Lynch syndrome is one of the most common hereditary cancer syndromes. Although Lynch syndrome is associated with increased risk for developing colorectal, endometrial, and other cancers specialized screening, risk-reducing surgery, and chemoprevention offer promise for reducing morbidity and mortality. Frequent colonoscopic surveillance has proven effective for early detection and prevention of Lynch syndrome-associated colorectal cancer; however, the optimal strategy for managing endometrial cancer risks in women with germline mutations in DNA mismatch repair genes has yet to be determined. In this issue of Cancer Prevention Research, Lu and colleagues report their findings of a phase II prospective, multicenter randomized trial comparing the effects of oral contraceptive pills and Depo-Provera on endometrial proliferation in women with Lynch syndrome. Although short-term hormonal treatment with either modality altered endometrial proliferation indices, it remains unknown whether hormonal suppression actually reduces endometrial cancer risk in women with Lynch syndrome. This trial represents the first of its kind in evaluating agents which might offer protection against Lynch syndrome-associated endometrial cancer and provides preliminary data regarding potential biomarkers for early detection of endometrial neoplasia. The investigators' experience with this trial also offers insights regarding the various technical and scientific challenges inherent in chemoprevention research.

Abstract A54: Can clinical criteria reliably distinguish between sporadic and Lynch Syndrome-associated endometrial carcinomas with immunohistochemical loss of MLH1?

Abstract Background: Lynch syndrome is a hereditary cancer syndrome caused by a germline defect in one of 4 DNA mismatch repair genes: MLH1, MSH2, MSH6, or PMS2. Hallmark tumors for this syndrome, endometrial and colorectal cancers, have a prevalence of 60-80% in affected individuals. Accurate identification of patients with this syndrome allows for cancer prevention measures to be instituted in the index patient as well as relatives that test positive for the mutation. Referral for genetic testing for Lynch syndrome is often based on clinical screening criteria, which includes young age of cancer diagnosis and a family history of Lynch syndrome associated tumors. Immunohistochemistry and microsatellite instability analysis have emerged as additional screening tools to assist in evaluating a tumor's probability of being sporadic or secondary to Lynch syndrome. This type of testing can either be used universally on all endometrial carcinomas as an initial triage step, or it can be used after clinical screening criteria has identified someone as at-risk. One limitation of using only microsatellite instability testing and immunohistochemistry is that 15-20% of sporadic endometrial and colorectal cancers have immunohistochemical loss of the DNA mismatch repair protein MLH1 and the presence of high levels of microsatellite instability due to methylation of MLH1 rather than germline mutation of MLH1. A follow up test, the PCR-based MLH1 methylation assay, assists in differentiating sporadic endometrial cancers from probable Lynch syndrome tumors in this subset exhibiting immunohistochemical loss of MLH1. A limitation of this assay is that it is PCR-based and may not be accessible to many smaller clinical laboratories. The objective of this study was to determine if Society of Gynecologic Oncology (SGO) clinical criteria were able to correctly distinguish between sporadic endometrial cancers (MLH1 methylated) from probable Lynch syndrome-associated endometrial cancer (MLH1 unmethylated). Methods: Patients with endometrial carcinomas that had undergone hysterectomy at our institution and had immunohistochemical testing for MLH1 and MLH1 promoter methylation analysis were included in this study. Electronic medical records were reviewed to obtain complete clinical and pathologic data for each case. SGO criteria, a modified form of the Revised Bethesda guidelines which uses endometrial cancer as the cancer of reference, were applied to all patients. Results: Of 337 endometrial carcinomas that underwent immunohistochemical evaluation of the four DNA mismatch repair proteins, 54 had immunohistochemical loss of MLH1. 40/54 had MLH1 methylation and were designated as sporadic, while 14/54 lacked MLH1 methylation and were designated as probable Lynch syndrome. In our cohort, 22/54 endometrial carcinoma patients had clinical features that fulfilled SGO criteria for further genetic evaluation, including germline testing for mutation of MLH1. The SGO criteria correctly identified 10/14 probable Lynch syndrome patients. The sensitivity and specificity of SGO criteria within this population were 71.4% and 69.2%, respectively. Conclusions: SGO criteria correctly identified 71% of Lynch syndrome-associated endometrial carcinomas with immunohistochemical loss of MLH1. In addition to missing nearly 30% of endometrial cancer patients with a likely diagnosis of Lynch syndrome, use of SGO criteria alone without the PCR-based MLH1 promoter methylation assay would result in an additional 12 individuals undergoing unindicated germline MLH1 mutational testing. Using the MLH1 methylation assay decreases the number of cases referred for germline testing to 14, thus making the clinical evaluation of these patients more cost effective. Our study highlights the importance of the MLH1 methylation assay in the evaluation of patients undergoing molecular diagnostic testing and evaluation for Lynch syndrome. Citation Format: Amanda S. Bruegl, Bojana Djordjevic, Diana Urbauer, Shannon N. Westin, Pamela T. Soliman, Karen H. Lu, Rajyalakshmi Luthra, Russell R. Broaddus. Can clinical criteria reliably distinguish between sporadic and Lynch syndrome-associated endometrial carcinomas with immunohistochemical loss of MLH1? [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A54.

Genetic Testing by Cancer Site

This review article discusses hereditary cancer predisposition syndromes with uterine manifestations. Lynch syndrome accounts for 2% to 3% of endometrial cancers. The identification of endometrial cancer patients at risk for Lynch syndrome is discussed, as are the characteristics of Lynch syndrome-associated endometrial cancer and the screening and prevention options for women at risk for Lynch syndrome-associated endometrial cancer. Endometrial cancer associated with PTEN hamartoma tumor syndrome (also known as Cowden syndrome) is also discussed. HLRCC (hereditary leiomyomatosis and renal cell carcinoma), which has an associated high risk of symptomatic uterine leiomyomas, is reviewed.

An alternative approach to identify women at risk for colorectal cancer.

1513 Background: Hereditary colorectal cancer (CRC) is preventable; however, identification of individuals at sufficiently high risk to warrant heightened surveillance is difficult. Lynch Syndrome (LS) is an inherited cancer syndrome due to germline mutation in a DNA mismatch repair gene. For women with LS, the lifetime risk of endometrial cancer (EC) is 64% and CRC is 54%. Fifty percent of women with LS will present with EC or ovarian cancer prior to CRC. Therefore, women with LS associated EC represent an ideal group for CRC prevention. The optimal method to identify women with LS associated EC is not known. The purpose of this study was to determine the utility of Amsterdam II and Society of Gynecologic Oncology (SGO) Criteria (modified Bethesda criteria that use EC as the sentinel cancer) in identifying women with LS associated EC. Our ultimate goal is to identify women at increased risk of CRC. Methods: Immunohistochemistry (IHC) for DNA mismatch repair proteins and MLH1 methylation analyses were used to identify LS associated EC among 388 women. EC was designated as LS if there was loss of mismatch repair protein expression. Absence of MLH1 methylation was required to confirm LS in tumors with MLH1 protein loss. Results: Fifty-nine (15.2%) of the EC patients tested had LS. These patients are summarized in the table. Conclusions: Clinical criteria to detect LS identify 17/59 (29%) - 44/59 (74%) of women who present with EC first. EC with MSH2 loss is most likely to occur in younger women and women with positive family history of EC and CRC, features classically associated with LS. In general, the MSH6 mutation is associated with older age at diagnosis and fewer familial CRCs, however, we found a large number of MLH1 (50%) and PMS2 (86%) cases diagnosed at greater than 50 years with no family history of CRC. Our data suggest that classic clinical screening criteria are inadequate to detect patients with LS who present with EC, potentially missing up to 25% of these patients. [Table: see text]

Molecular analysis of endometrial pathogenesis in Lynch syndrome.

5095 Background: Women with Lynch Syndrome (LS) have a 40-60% predicted lifetime risk of developing endometrial cancer (EC). We hypothesize that in LS-associated EC, normal endometrium accumulates molecular changes in a step-wise fashion similar to sporadic EC. The objective of this study was to investigate precursor lesions and identify molecular changes contributing to endometrial carcinogenesis in LS-associated EC. Methods: Women with a confirmed mismatch repair gene mutation for LS undergoing a prophylactic or therapeutic hysterectomy were eligible. Case controls were matched 2:1 for EC and hyperplasia based preferentially on age and histology. Molecular analysis of PIK3CA, KRAS, AKT, and CTNNB1 was performed using Sequenom MassArray system. PTEN expression was assessed by immunohistochemistry. Statistical analysis was performed using Fisher’s exact test. Results: There were 67 patients with LS (30 normal endometrium, 8 hyperplasia, 39 EC) and 84 patients (10 normal endometrium, 16 hyperplasia, 58 EC) in the case matched control group. Concurrent complex atypical hyperplasia (CAH) was found in EC in 11 (39.3%) and 21 (46.6%) of LS and sporadic cases respectively. Loss of PTEN expression did not differ between sporadic (69%) and LS EC (86.2%) (p=0.117). However, sporadic CAH demonstrated 68.8% PTEN loss compared to only 12.5% in LS CAH (p=0.056). There was no difference in KRAS frequency in sporadic EC (10.3%) compared to LS EC (3.4%) (p=0.416). PIK3CA mutations occurred more frequently in sporadic EC (39.7%) compared to LS EC (13.8%) (p=0.015). Sporadic EC (37.9%) had significantly more CTNNB1 mutations than LS EC (6.9%) (p= 0.002). There was no relationship between PIK3CA, KRAS, AKT and CTNNB1 mutation and loss of PTEN expression. Conclusions: Similar to sporadic EC, hyperplasia is part of the pre-invasive spectrum of disease in LS associated EC. While PTEN loss was common in both LS and sporadic EC, PIK3CA and CTNNB1 mutations were more frequent in sporadic EC than LS EC. Our results indicate that loss of PTEN expression is an early event in sporadic EC and that other common mutations in sporadic EC may have a lesser role in LS associated EC development.

Endometrial cancer and Lynch syndrome: clinical and pathologic considerations.

Approximately 2% to 5% of endometrial cancers may be due to an inherited susceptibility. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, an autosomal-dominant inherited cancer susceptibility syndrome caused by a germline mutation in one of the DNA mismatch repair genes, accounts for the majority of inherited cases. Lynch syndrome is associated with early onset of cancer and the development of multiple cancer types, particularly colon and endometrial cancer. The current status of knowledge regarding Lynch syndrome-associated endometrial cancer and methods for diagnosis, screening, and prevention of cancers is reviewed. The lifetime cumulative risk of endometrial cancer for women with Lynch syndrome is 40% to 60%, which equals or exceeds their risk of colorectal cancer. No current evidence suggests either a survival advantage or disadvantage to endometrial cancer that is associated with Lynch syndrome when these cases are compared with sporadic cases. A combination of family and personal medical history and tumor testing provides an efficient basis for diagnosing Lynch syndrome in women with endometrial cancer. Current gynecologic cancer screening guidelines for women with Lynch syndrome include annual endometrial sampling and transvaginal ultrasonography beginning at age 30 to 35 years. Diagnosing endometrial cancer patients with Lynch syndrome has important clinical implications for the individual and family members. Screening and prevention practices can decrease the likelihood of developing additional cancers.