Mismatch repair protein deficiency in endometriosis: Precursor of endometriosis-associated ovarian cancer in women with lynch syndrome

ObjectiveWe aimed to elucidate the pathogenesis of ovarian cancer through the loss of mismatch repair (MMR) proteins in women with Lynch syndrome (LS) in this report.Case reportTwo women with LS underwent surgery for synchronous endometrial cancer and ovarian cancer. In both cases, immunohistochemical examination showed concomitant MMR protein deficiency in endometrial cancer, ovarian cancer, and contiguous ovarian endometriosis. In Case 1, the macroscopically normal ovary included multiple endometrioses with MSH2 and MSH6 expression, and FIGO grade 1 endometrioid carcinoma and contiguous endometriosis without MSH2 and MSH6 expression. In Case 2, all endometriotic cells contiguous with carcinoma in the lumen of the ovarian cyst showed loss of the expression of MSH2 and MSH6.ConclusionOvarian endometriosis with MMR protein deficiency may progress to endometriosis-associated ovarian cancer in women with LS. Diagnosing endometriosis in women with LS during surveillance is important.     

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients

ObjectiveLynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV.Methods341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13–12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified.ResultsTwenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total).ConclusionsSince double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.     

林奇综合征相关子宫内膜癌研究进展

林奇综合征（lynch syndrome,LS）是一种常染色体显性遗传病,既往称为遗传性非息肉病性结直肠癌（hereditary nonpolyposis colorectal cancer,HNPCC）,是由DNA错配修复（mismatch repair,MMR）基因MLH1、MSH2、MSH6和PMS2的胚系突变引起。LS患者有多种癌变倾向、发病低龄化及家族易感性,可同时或异时发生结直肠癌、子宫内膜癌（endometrial cancer,EC）、卵巢癌、胃癌和乳腺癌等,女性患者中EC与之最为密切,目前我国对于LS相关EC（LS-EC）认识尚不足,并未形成完整的诊疗标准或指南。为提高对LS-EC的认识,综述LS-EC的分子机制、临床病理特征、筛查及诊断、临床治疗手段、预防等。     

Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤ 70 years

Objective

Lynch syndrome (LS) is a hereditary syndrome that predisposes to multiple malignancies including endometrial cancer (EC). We aimed to evaluate a diagnostic strategy for LS based on routine analysis of microsatellite instability (MSI) and immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in tumour tissue of all newly diagnosed EC patients ≤ 70 years.

Methods

Consecutive EC patients ≤ 70 years were included prospectively in eight Dutch centres. EC specimens were analysed for MSI, IHC of four MMR proteins, MMR gene methylation status and BRAF-mutations. tumours were classified as; 1) likely to be caused by LS, 2) sporadic MSI-H, or 3) microsatellite stable (MSS).

Results

Tumour specimens of 179 patients (median age 61 years, IQR 57-66) were analysed. In our study 92% of included patients were over 50 years of age. Eleven EC patients were found likely to have LS (6%; 95% CI 3-11%), including 1 patient suspected of an MLH1, 2 of an MSH2, 6 of an MSH6 and 2 of a PMS2 gene defect. Germline mutation analyses revealed 7 MMR gene germline mutations. Ten patients likely to have LS (92%) were older than 50 years. In addition, 31 sporadic MSI-H tumours with MLH1 promoter hypermethylation (17%; 95% CI 13-24%) were identified.

Conclusions

Molecular screening for LS in patients with EC diagnosed ≤ 70 years, leads to identification of a profile likely to have LS in 6% of cases. New screening guidelines for LS are needed, including recommendations for EC patients older than 50 years of age.     

Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer

ObjectiveIn the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline.MethodsFrom the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016–1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS.ResultsIn 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles.ConclusionCoverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients.     

Mismatch repair deficiency in ovarian cancer — Molecular characteristics and clinical implications

DNA mismatch repair (MMR) deficiency is associated with increased risk of developing several types of cancer and is the most common cause of hereditary ovarian cancer after BRCA1 and BRCA2 mutations. While there has been extensive investigation of MMR deficiency in colorectal cancer, MMR in ovarian cancer is relatively under-investigated. This review summarizes the mechanism of MMR, the ways in which MMR deficiency can promote carcinogenesis in general and then assesses the available studies regarding MMR deficiency in ovarian cancers with specific emphasis on implications for disease incidence and therapy. The incidence of germline MMR gene mutations in ovarian cancer is only 2% but other mechanisms of gene inactivation mean that loss of expression of one of the seven main genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2) occurs in up to 29% of cases. Both mutational and expression data suggest that MMR deficiency is more common in non-serous ovarian cancer. Some studies suggest an improved survival for patients with MMR deficiency compared to historical controls but these do not account for the preponderance of non-serous tumors. A number of in vitro studies have suggested that MMR deficiency is a cause of platinum resistance. To date this has not been categorically demonstrated in the clinic. Larger studies that account for stage of presentation and immunohistochemical subtype are required to assess the effect of MMR deficiency on survival and chemosensitivity. Investigation of MMR related synthetic lethality in colorectal cancer has identified dihydrofolate reductase, DNA polymerase β and DNA polymerase γ and PTEN-induced putative kinase 1 as synthetic lethal to certain MMR defects by causing accumulation of oxidative DNA damage. These synthetic lethal targets require tested and others should be sought within the context of MMR deficient ovarian cancer in an attempt to provide novel therapeutic strategies for these patients.     

Lynch Syndrome in patients with clear cell and endometrioid cancers of the ovary

Objective

Patients with Lynch Syndrome are at an increased risk for a variety of malignancies, including ovarian cancer. Ovarian cancers associated with Lynch Syndrome are predominantly clear cell or endometrioid in histology. Lynch Syndrome is characterized by germline mutations in mismatch repair (MMR) genes. The current study aims to assess the prevalence of loss of MMR expression in patients with endometrioid and clear cell ovarian carcinoma.

Methods

A retrospective review identified 90 patients with endometrioid and/or clear cell carcinomas. Slides made from tumor tissue microarray blocks were evaluated using immunohistochemical stains with antibodies against MLH1, PMS2, MSH2, and MSH6. Statistical analysis was performed.

Results

Seven of the 90 cases (7.8%) had loss of MMR expression. The mean age of patients with loss of MMR expression (47 years) was significantly younger than those with retained MMR expression (p = 0.014). Loss of MMR expression was present in 20% of patients under the age of 53 with clear cell or endometrioid cancers. Genetic studies found that 3 of the 5 patients with loss of MMR expression carried mutations consistent with Lynch Syndrome; acquired hypermethylation of MLH1 was noted in one patient. Six of 7 patients (86%) whose tumors lacked MMR expression had synchronous or metachronous primary malignancies, a significantly greater prevalence than those with retained MMR expression (p < 0.001).

Conclusion

Patients under the age of 53 with clear cell or endometrioid ovarian carcinomas are at a clinically significant risk for loss of MMR expression and Lynch Syndrome; routine screening with immunohistochemical staining should be considered.     

Lynch Syndrome Screening of Women with Endometrial Cancer: Feasibility and Outcomes in a Community Program

ObjectiveUniversal screening of endometrial cancer for underlying Lynch syndrome (LS) using DNA mismatch repair immunohistochemistry (MMR IHC) has been recommended. The objective of this study was to assess the feasibility and outcomes of using office endometrial samplings in a community LS screening program.MethodsA community laboratory adopted Cancer Care Ontario's LS screening recommendations. All new endometrial cancers in women aged <70 years were screened for LS using MMR IHC and MLH1 promoter methylation testing cascade for MLH1/PMS2-deficient cases. This retrospective validation study analyzes the first year's results.ResultsOf 693 new endometrial cancers, 467 (67.4%) were eligible for LS screening. Both MMR IHC and MLH1 promoter methylation testing were conclusive in >98% of cases. MMR deficiency (MMRd), which includes LS screen-positive cases, was identified in 25.9% of patients (121/467). LS screen-positive tumours comprised 5.9% (27/467) of all cases.ConclusionEndometrial samplings from community practice are suitable for pre-operative LS screening. This testing can identify MMRd endometrial cancers with significant prognostic implications. Approximately 1 in 20 Ontario women <70 years of age with endometrial cancer screen positive for LS. Pre-operative and/or operative assessment for co-existent colonic neoplasms needs to be considered in this high-risk group. In addition, these women should be referred to genetic counselling.     

Two Japanese kindreds occurring endometrial cancer meeting new clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC), Amsterdam Criteria II

Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominantly inherited disorder of cancer susceptibility. Patients with HNPCC exhibit an increased risk for HNPCC-associated extracolonic tumors such as cancer of the endometrium. HNPCC is associated with germline mutations in DNA mismatch repair (MMR) genes: hMLH1, hMSH2 and hMSH6. Here, we describe two Japanese kindreds (0.5%) who met the new clinical criteria for HNPCC, Amsterdam criteria II, from among 375 endometrial cancer patients treated at Keio University Hospital from 1990 to 2002. From these results, it was found that female HNPCC patients comprised approximately 0.5% of all endometrial cancer patients. Decreased expression of two MMR gene protein products (hMLH1 and hMSH6) was confirmed immunohistochemically in these two endometrial tumors in HNPCC kindreds. This case report provides important information on Japanese HNPCC patients occurring endometrial cancer.     

The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer

OBJECTIVE: Ovarian cancer has one of the highest fractions of hereditary cases. The hereditary breast and ovarian cancer syndrome, primarily due to mutations in BRCA1 and BRCA2, is the main cause of heredity, but also the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome confers an increased risk of ovarian cancer. In order to clarify the contribution of HNPCC to the development of ovarian cancer, we collected data on family history of cancer and characterized MMR function in a consecutive series of 128 tumors unselected for age at diagnosis and previously characterized for BRCA gene mutations. METHODS: Expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry using tissue microarray sections. Tumors with reduced staining or loss of staining were also analyzed for microsatellite instability (MSI). RESULTS: Loss of MMR protein expression was identified in 3 ovarian cancers, all of which had a MSI-high phenotype. DNA sequence analysis revealed disease-causing germline mutations (deletions of exons 4-6 in MLH1 and a 1-nucleotide deletion in exon 5 of MSH6) in two patients diagnosed at ages 40 and 49 years, both of whom had family histories suggestive of HNPCC. The genetic defect in the third case, which was a 47-year old woman without knowledge about her family history with loss of MLH1/PMS2 expression in the tumor tissue, remains elusive. A family history suggestive of HNPCC was identified in an additional case, but this tumor showed normal, retained MMR protein expression and a microsatellite stable phenotype. CONCLUSIONS: About 2% of ovarian cancer is caused by germline mutations in the MMR-genes, a minor proportion as compared to the contribution of the BRCA-genes (11% in the present series). However, identification of HNPCC patients is important since it allows inclusion of high-risk individuals into control programs aimed at preventing the more frequent colorectal and endometrial cancers. Tumors within the HNPCC-spectrum should therefore be included when recording a family history of cancer among patients diagnosed with ovarian cancer.     

Risk factors for HPV infection among American Indian and White women in the Northern Plains

Introduction

Immunohistochemistry (IHC) for the presence or absence of DNA mismatch repair (MMR) proteins in tumor samples is a quick and relatively inexpensive method to screen for Lynch syndrome (LS). At our institution we have found that > 20% of patients lack expression of MMR proteins and > 10% would be expected to benefit from genetic counseling (GC). However, compliance with referral to GC is poor. Therefore, we set out to analyze the reasons for noncompliance, hypothesizing that it could be due to a perception of a low risk for developing other cancers.

Methods

All patients with endometrial cancer between 2007 and 2009 were identified. Patients with absence of MMR protein expression who would be expected to benefit from GC were identified. These patients were sent a questionnaire assessing the utilization of GC services as well as their perception of LS and Lynch-associated cancers.

Results

Forty-seven patients out of 384 were identified who would have been expected to benefit from GC. Of the responders, 20 patients (77%) reported that they were referred by their physician for GC, of which 9 saw a genetic counselor, 8 had genetic testing, and 3 mutations were detected. The primary reason for not seeing a genetic counselor was no insurance coverage/cost of the visit followed by anxiety for the results. Nine patients stated that the patient/family did not want to know information regarding cancer risk. As compared to the general population 35% thought their risk of having LS was higher, 12% thought it was the same, 15% lower, and 38% was unsure. Forty-six percent of patients thought the risk of colon cancer was higher than background risk, and 26% thought it was the same.

Conclusion

Most patients underestimate their risk of LS associated heritable cancer. Physicians should pay more attention to family history and IHC in order to refer patients appropriately. In addition, more verbal and written information may enable patients to accurately assess their cancer risk. This could further improve compliance with genetic counseling and detection of Lynch syndrome.     

不同分子学筛查方法在Lynch综合征相关子宫内膜癌患者中的对比分析#br#

Objective?Compare the accuracy of immunohistochemical staining (IHC), microsatellite instability detection (MSI), and the combined detection of the two in the screening of Lynch Syndrome-related endometrial cancer (LS-EC), and analyze the advantages and disadvantages of actual clinical applications, to identify a routine and reasonable screening strategy. This study also reveals the incidence of LS-EC and the mutations of different mismatch repair (MMR) genes in the Chinese population in this region. Methods?IHC MMR protein detection and MSI detection were performed on the pathological tissues of diagnosed EC patients from the Second Hospital of Jilin University from November 2019 to November 2020, and the preoperative venous blood was subjected to next-generation sequencing (NGS) of Lynch syndrome-related mutations. Results?After NGS testing, 8 cases of LS were confirmed, with an incidence rate of 7.90%. 28 cases had lack of expression of MMR protein, 7 cases were diagnosed as LS, 1 case was missed diagnosis; 13 cases had high microsatellite instability (MSI-H), 3 cases were diagnosed as LS, 5 cases were missed; the combined detection of the two tests can screen out all LS patients. Conclusion?IHC combined with MSI screening is highly sensitive but not cost-effective. IHC alone is recommended as the first clinical screening method.     

Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors

Objective

Heredity is a major cause of ovarian cancer and during recent years the contribution from germline mismatch repair (MMR) gene mutations linked to Lynch syndrome has gradually been recognized.

Methods

We characterized clinical features, tumor morphology and mismatch repair defects in all ovarian cancers identified in Swedish and Danish Lynch syndrome families.

Results

In total, 63 epithelial ovarian cancers developed at mean 48 (range 30-79) years of age with 47% being early stage (FIGO stage I). Histologically, endometrioid (35%) and clear cell (17%) tumors were overrepresented. The underlying MMR gene mutations in these families affected MSH2 in 49%, MSH6 in 33% and MLH1 in 17%. Immunohistochemical loss of the corresponding MMR protein was demonstrated in 33/36 (92%) tumors analyzed.

Conclusion

The combined data from our cohorts demonstrate that ovarian cancer associated with Lynch syndrome typically presents at young age as early-stage, non-serous tumors, which implicates that a family history of colorectal and endometrial cancer should be specifically considered in such cases.     

子宫内膜癌中错配修复(MMR)蛋白表达缺失筛查Lynch综合征及其临床病理特点

目的:通过分析比较子宫内膜癌患者的错配修复(MMR)蛋白表达缺失的情况,研究其与临床标准诊断之间的关系,以及MMR蛋白表达缺失者的临床病理特征。方法:收集北京大学第一医院2011年12月至2015年7月收治的313例子宫内膜癌患者的临床资料,免疫组化法分析子宫内膜癌组织中MMR蛋白(MLH1/MSH2/MSH6/PMS2)表达情况。结果:临床诊断或可疑的Lynch综合征22例(7.0%),存在MMR表达缺失者49例(15.7%)。临床诊断或可疑Lynch的患者中,存在MMR表达缺失者的比例明显升高(P=0.011),其中主要是MSH6表达缺失存在差异(P=0.004)。MSH2表达缺失和MSH6表达缺失的患者中合并高血压的比例更低(P=0.002,P=0.045)、淋巴结转移的比例更高(P=0.025,P=0.020)、肿瘤分化差(P=0.030,P=0.010);MSH6表达缺失的患者,相对年龄更小(P=0.021)。结论:免疫组化检测MMR蛋白表达缺失在诊断或可疑Lynch综合征患者中的比例更高,可用于辅助进行Lynch综合征的筛查及诊断。MMR蛋白表达缺失与患者低龄、存在淋巴结转移、肿瘤分化不良等临床病理特征相关。     

Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for lynch syndrome

Objective

Determine factors impacting the uptake of genetic counseling and results of genetic testing following universal tumor testing for Lynch syndrome in patients with endometrial cancer.

Methods

The study population consisted of two unselected cohorts of endometrial cancer patients, 408 identified retrospectively and 206 identified prospectively. Immunohistochemistry for mismatch repair protein expression and/or microsatellite instability analysis was performed on these tumors. MLH1 methylation analysis was performed on tumors with loss of MLH1 protein. Tumor studies were considered suggestive of Lynch Syndrome if they showed immunohistochemical loss of MSH2, MSH6 or PMS2, loss of MLH1 without MLH1 promoter methylation, and/or microsatellite instability. Participants with suggestive tumor studies were contacted and offered genetic counseling and testing.

Results

In the retrospective cohort, 11% had tumor studies suggestive of Lynch syndrome, and 42% was seen for genetic counseling. A germline mutation was detected in 40%, and one had a variant of uncertain significance. In the prospective cohort, 8.7% of patients had tumor testing suggestive of Lynch syndrome; 72% were seen for genetic counseling. Germline mutations were found in 40%, and one had a variant of uncertain significance. Common challenges included timing of re-contact, age, perceived lack of relevance, inability to travel and limited insurance coverage.

Conclusions

There are several barriers to genetic counseling and testing follow-up after universal tumor testing, and uninformative genetic test results present a management challenge. It is important to consider these limitations when implementing an approach to screening endometrial cancer patients for Lynch syndrome.     

Universal screening for Lynch syndrome in uterine cancer patients: A quality improvement initiative

ObjectiveTo determine the feasibility and effectiveness of a quality improvement initiative (QI) to adopt universal screening for Lynch syndrome in uterine cancer patients at an institution that previously employed age-based screening.MethodsPrior to the initiative, tumors of patients with uterine cancer diagnosed at age ≤ 60 years were screened for mismatch repair deficiency (MMR) and microsatellite instability (MSI). The QI process change model adopted universal testing of all uterine cancer specimens and implemented provider training, standardized documentation, and enhanced use of the electronic medical record (EMR). We compared screening rates, results of screening, follow up of abnormal results, and final diagnoses from the pre- and post-implementation periods.ResultsPre- and post-implementation screening rates for women age ≤ 60 years at the time of diagnosis were 45/78 (57.7%) and 64/68 (94.5%), respectively. The screening rate for all patients with uterine cancer increased from 73/190 (38.4%) to 172/182 (94.5%). The rate of abnormal screening results increased from 15/190 (7.9%) to 44/182 (24.0%) cases. Genetics referral rates among screen positives increased from 3/15 (20.0%) to 16/44 (36.4%). Germline diagnoses increased from 2/190 (1.1%) with two Lynch syndrome diagnoses to 4/182 (2.2%) including three Lynch syndrome diagnoses and one BRCA1 germline diagnosis. The number of patients errantly not screened decreased from at least 32 patients to 3 patients after the intervention.ConclusionsAdherence to screening guidelines significantly improved after interventions involving provider education, optimal use of the EMR, and simplification of screening indications. These interventions are feasible at other institutions and translatable to other screening indications.     

MSH2 splice site mutation and endometrial cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited syndrome of cancer susceptibility caused by germ line mutations of genes participating in mismatch repair (MMR). Carriers of MMR gene mutations have an increased risk of colorectal cancers and cancer of other organs. Tumors of the endometrium represent the most frequent extracolonic malignancies in HNPCC. It has been suggested that women harboring MMR gene mutations have a higher risk of endometrial cancer than of colon cancer. Here, we describe an HNPCC patient with early-onset endometrial cancer and a strong familial history of endometrial tumors who harbored a germ line MSH2 splice site mutation (IVS9_2A>G). This mutation was responsible for abnormal messenger RNA processing, leading to the introduction of a premature stop signal and to the expression of a truncated MSH2 protein. In addition, the same mutation was associated with loss of MSH2 protein expression, high microsatellite instability, and PTEN inactivation. Although a direct relationship between the endometrial cancer susceptibility and the MSH2 mutation we found cannot be established, our observations, consistent with the work of other authors, suggest the involvement of germ line MSH2 abnormalities in endometrial tumor development and support the case for endometrial cancer screening in women from HNPCC families.     

Association of immunohistochemical profiles with histotypes in endometrial carcinomas

ObjectiveAlthough a large number of endometrial cancer patients are cured with surgery alone, there are significant numbers of patients with more aggressive variants of endometrial carcinoma for whom the prognosis remains poor. We investigated the effects of prevalence, histotypes, and immunohistochemical profiles on prognostic value in a hospital-based population.Materials and methodsA retrospective study of surgically resected primary endometrial carcinoma was included. Immunohistochemical stains were performed on formalin-fixed paraffin-embedded tissue microarray sections for β-Catenin, estrogen receptor (ER), progesterone receptor (PR), HER-2, MLH1, MSH2, MSH6, PMS2, and p53.ResultsLoss of mismatch repair expression was detected in 25.4% of samples (29/114, mean age 57 years) of the tumors. The following loss of expression was observed in patients: MLH1/PMS2 in 16.6% of patients, MSH6 in 7.0% of patients, MLH1 in 0.9% of patients, and MSH6/PMS2/MLH1 in 0.9% of patients. Immunohistochemistry of p53 was analyzed for 111 patients. A total of 13 patients (11.7%, mean age 64 years) had p53-abnormal expression (absent, cytoplasmic or diffuse strong positive patterns), and more than half (9/13, 69.2%) had endometrioid histotype. Abnormalities in p53 were significantly associated with histotype (p = 0.001), advanced tumor stage (p = 0.038), death of disease (p = 0.002), PR percentage (p = 0.002), and HER-2 expression (p = 0.018). Immunohistochemical nuclear localization of β-Catenin was detected in 7.1% of the cohort. The combination of p53 and nuclear β-Catenin expressions was not significantly predictive of disease-free or overall survival.ConclusionThe results of this study are useful for management of endometrial cancer in patients with DNA mismatch repair, abnormal p53 expression, or nuclear localization of β-Catenin.     

Screening and diagnosis of endometrial cancer in Lynch syndrome

Lynch syndrome (LS) is an autosomal dominant inherited cancer predisposition syndrome caused by a mismatch of DNA repair (MMR system). Lifetime risk of developing endometrial and ovarian cancer in LS is higher than in the general population and gynecologic screening appears interesting. Screening is based on several tests: pelvic ultrasound, endometrial biopsy and hysteroscopy for endometrial cancer, pelvic ultrasound and CA125 for ovarian cancer. Those tests appear efficient for the diagnosis of gynecologic cancers in LS. Nevertheless, screening tests have not proved clinical benefit until now, and potential problems of compliance, risk of false negative cases, and interval cancer associated with screening do justify offering prophylactic surgery to patients. Women with LS should be informed of the potential benefits and risks of screening and the importance of evaluation in case of gynecologic symptoms or abnormal bleeding. Chemoprevention by progestin-containing oral contraceptives and the treatment of premalignant lesion are available options for reducing the risk of endometrial cancer in LS population.     

Women with breast and uterine cancer are more likely to harbor germline mutations than women with breast or uterine cancer alone: A case for expanded gene testing

ObjectiveWe explored the germline mutation spectrum and prevalence among 1650 women with breast and uterine cancer (BUC) who underwent multi-gene hereditary cancer panel testing at a single commercial laboratory.MethodsThe combined frequency of mutations in 23 BC and/or UC genes was compared between BUC cases and control groups with (1) no personal cancer history; (2) BC only; and (3) UC only using logistic regression.ResultsFourteen percent (n = 231) of BUC cases tested positive for mutations in BC and/or UC genes and were significantly more likely to test positive than individuals with BC only (P < 0.001), UC only (P < 0.01), or unaffected controls (P < 0.001). Analysis of gene-specific mutation frequencies revealed that MSH6, CHEK2, BRCA1, BRCA2, ATM, PMS2, PALB2 and MSH2 were most frequently mutated among BUC cases. Compared to BC only, BRCA1, MLH1, MSH2, MSH6, PMS2 and PTEN mutations were more frequent among BUC; however, only ATM mutations were more frequent among BUC compared to UC only. All of the more commonly mutated genes have published management guidelines to guide clinical care. Of patients with a single mutation in a gene with established testing criteria (n = 152), only 81.6% met their respective criteria, and 65.8% met criteria for multiple syndromes.ConclusionsWomen with BUC are more likely to carry hereditary cancer gene mutations than women with breast or uterine cancer alone, potentially warranting expanded genetic testing for these women. Most mutations found via multi-gene panel testing in women with BUC have accompanying published management guidelines and significant implications for clinical care.