Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?

e17119 Background: Universal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer (EC) to identify those with underlying Lynch syndrome (LS). However, since its implementation in 2013, the effectiveness of this screening method on identifying individuals with LS across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), MLH1 methylation, and microsatellite instability (MSI) analysis among EC patients. Methods: We conducted a complete systematic search of online databases PubMed, Embase, Medline, and Cochrane Library between 1990-2018. A DerSimonian–Laird random-effects model meta-analysis was utilized to estimate the weighted prevalence of LS diagnoses. Results: The comprehensive search produced 3,427 publications. 29 peer-review studies met the inclusion criteria. 6,649 EC patients were identified, 206 (3%) were confirmed to have LS following positive universal tumor molecular screening.5,917 patients underwent tumor IHC, 28% had abnormal staining. 3,140 patients underwent MSI analysis, 31% had MSI instability. Among EC patients with deficient IHC staining or positive MSI analysis, the weighted prevalence of LS was 15% and 19% respectively. 1159 patients exhibited loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation negative, 32 demonstrated a germline MLH1 mutation (2.8% of all MLH1 absent staining; 22.4% of all MLH1 methylation negative). 43% of EC patients diagnosed with LS via tumor typing would have been missed by family history-based screening alone. Conclusions: Despite widespread implementation of universal tumor testing in EC, data regarding results have previously been limited. For the first time, this study provides large-scale predictive values that will help practitioners evaluate abnormal results in the context of LS and aid in patient counseling. [Table: see text]

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Understanding Inherited Risk in Unselected Newly Diagnosed Patients With Endometrial Cancer

JCO Precision Oncology ◽

10.1200/po.18.00338 ◽

2019 ◽

pp. 1-15

Author(s):

Karen A. Cadoo ◽

Diana L. Mandelker ◽

Semanti Mukherjee ◽

Carolyn Stewart ◽

Deborah DeLair ◽

...

Keyword(s):

Endometrial Cancer ◽

Next Generation Sequencing ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Cancer Predisposition ◽

Next Generation ◽

Germline Variants ◽

Predisposition Genes ◽

Generation Sequencing

PURPOSE Mutations in DNA mismatch repair genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We determined the prevalence of pathogenic germline variants in unselected patients with endometrial cancer scheduled for surgical consultation. PATIENTS AND METHODS Patients prospectively consented (April 2016 to May 2017) to an institutional review board–approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel—the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets—that yielded germline results for more than 75 cancer predisposition genes. Tumors were assessed for microsatellite instability. Per institutional standards, all tumors underwent Lynch syndrome screening via immunohistochemistry (IHC) for mismatch repair proteins. RESULTS Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. In 104 patients (67%), tumors were endometrioid, and 60 (58%) of those tumors were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%): seven (4.5%) had highly penetrant cancer syndromes and 15 (9.6%) had variants in low-penetrance, moderate-penetrance, or recessive genes. Of these, five (21%) were in Lynch syndrome genes (two MSH6, two PMS2, and one MLH1). All five tumors had concordant IHC staining; two (40%) were definitively microsatellite instability–high by next-generation sequencing. One patient had a known BRCA1 mutation, and one had an SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in low- and moderate-penetrance variants or genes associated with recessive disease. CONCLUSION In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multigene panel testing identified cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations.

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Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, andMLH1methylation improved the diagnosis of Lynch syndrome across the population?

Cancer ◽

10.1002/cncr.32203 ◽

2019 ◽

Vol 125 (18) ◽

pp. 3172-3183 ◽

Cited By ~ 8

Author(s):

Ryan M. Kahn ◽

Sushmita Gordhandas ◽

Brandon Paul Maddy ◽

Becky Baltich Nelson ◽

Gulce Askin ◽

...

Keyword(s):

Endometrial Cancer ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Cancer Tumor

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Prospective Determination of Prevalence of Lynch Syndrome in Young Women With Endometrial Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.10.8597 ◽

2007 ◽

Vol 25 (33) ◽

pp. 5158-5164 ◽

Cited By ~ 160

Author(s):

Karen H. Lu ◽

John O. Schorge ◽

Kerry J. Rodabaugh ◽

Molly S. Daniels ◽

Charlotte C. Sun ◽

...

Keyword(s):

Endometrial Cancer ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Germline Mutation ◽

Age Of Onset ◽

Cancer Syndrome ◽

Degree Relative ◽

Entire Cohort ◽

Tumor Studies ◽

The Mean

Purpose Age younger than 50 years at the time of colon cancer diagnosis is often used as a screening criterion for Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). The purpose of this study was to determine the prevalence of MLH1, MSH2, and MSH6 mutations in an unselected cohort of women diagnosed with endometrial cancer at age younger than 50 years. Methods A prospective, multicenter study was performed at three institutions. After written consent was obtained, germline mutation testing by full sequencing and large deletion analysis of the MLH1, MSH2, and MSH6 genes was performed. Tumor studies included immunohistochemistry of MLH1, MSH2, and MSH6; microsatellite instability analysis; and hypermethylation of the MLH1 promoter. Results Of the 100 women, nine (9%; 95% CI, 4.2 to 16.4) carried a deleterious germline mutation: seven women with mutations in MSH2, one woman with a mutation in MLH1, and one woman with a mutation in MSH6. Two additional women had molecular studies consistent with the diagnosis of Lynch syndrome. The mean body mass index (BMI) for the entire cohort was 34.4, which is significantly higher than 29.2, the mean BMI for the mutation carriers. Predictors of finding a germline mutation included having a first-degree relative with a Lynch syndrome–associated cancer, endometrial tumor with loss of MSH2 expression, tumors with high microsatellite instability, and lower BMI. Conclusion In this prospective study of endometrial cancer patients younger than age 50 years, 9% were found to carry germline Lynch syndrome–associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome–associated germline mutation in MLH1, MSH2, and MSH6.

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Diagnostic value of microsatellite instability analysis in uterine cavity washings to detect endometrial cancer in Lynch syndrome

Gynecologic Oncology ◽

10.1016/j.ygyno.2013.04.297 ◽

2013 ◽

Vol 130 (1) ◽

pp. e101

Author(s):

A. Bats ◽

H. Blons ◽

C. Narjoz ◽

M. Le Frère-Belda ◽

P. Laurent-Puig ◽

...

Keyword(s):

Endometrial Cancer ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Uterine Cavity ◽

Diagnostic Value ◽

Instability Analysis ◽

Microsatellite Instability Analysis

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Examining patterns of genetic evaluation as well as the prevalence of tumor Mismatch Repair Deficiency or Microsatellite Instability and Lynch Syndrome in Women with Endometrial Cancer in New Orleans

Gynecologic Oncology ◽

10.1016/j.ygyno.2019.11.089 ◽

2020 ◽

Vol 156 (3) ◽

pp. e28-e29

Author(s):

P. Nair ◽

M. McDougal ◽

T. Weiss ◽

A. Jernigan

Keyword(s):

Endometrial Cancer ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

New Orleans ◽

Mismatch Repair ◽

Genetic Evaluation ◽

Mismatch Repair Deficiency ◽

Repair Deficiency

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Brief family history questionnaire to screen for Lynch syndrome in women with newly diagnosed non-serous, non-mucinous ovarian cancers

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2021-003082 ◽

2022 ◽

pp. ijgc-2021-003082

Author(s):

Soyoun Rachel Kim ◽

Alicia Tone ◽

Raymond Kim ◽

Matthew Cesari ◽

Blaise Clarke ◽

...

Keyword(s):

Ovarian Cancer ◽

Family History ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Extended Family ◽

Screening Strategy ◽

Newly Diagnosed ◽

Predictive Values ◽

Family History Questionnaire ◽

Sensitivity Specificity

ObjectivesWhile ovarian cancer is the third most common Lynch syndrome-associated cancer in women, there is no established screening strategy to identify Lynch syndrome in this population. The objective of this study was to assess whether the 4-item brief Family History Questionnaire can be used as a screening tool to identify women with ovarian cancer at risk of Lynch syndrome.MethodsIn this prospective cohort study, participants with newly diagnosed non-serous, non-mucinous ovarian cancer completed the brief Family History Questionnaire, extended Family History Questionnaire, and had tumors assessed with immunohistochemistry for mismatch repair proteins, MLH1 methylation, and microsatellite instability testing. All underwent universal germline testing for Lynch syndrome. Performance characteristics were compared between the brief Family History Questionnaire, extended Family History Questionnaire, immunohistochemistry±MLH1 methylation, and microsatellite instability testing.ResultsOf 215 participants, 169 (79%) were evaluable with both the brief Family History Questionnaire and germline mutation status; 12 of these 169 were confirmed to have Lynch syndrome (7%). 10 of 12 patients (83%) with Lynch syndrome were correctly identified by the brief Family History Questionnaire, compared with 6 of 11 (55%) by the extended Family History Questionnaire, 11 of 13 (85%) by immunohistochemistry±MLH1 methylation, and 9 of 11 (82%) by microsatellite instability testing. The sensitivity, specificity, positive predictive values, and negative predictive values of the brief Family History Questionnaire were 83%, 65%, 15%, and 98%, respectively. A combined approach with immunohistochemistry and the brief Family History Questionnaire correctly identified all 12 patients with Lynch syndrome. The brief Family History Questionnaire was more sensitive than the extended Family History Questionnaire and took <10 min for each patient to complete.ConclusionsThe brief Family History Questionnaire alone or combined with immunohistochemistry may serve as an adequate screening strategy, especially in centers without access to universal tumor testing.

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A KRAS hot spot mutation correlates with MLH1 methylation in endometrial carcinomas with microsatellite instability: A potential triage tool for Lynch syndrome evaluation

Gynecologic Oncology ◽

10.1016/j.ygyno.2014.03.214 ◽

2014 ◽

Vol 133 ◽

pp. 79-80

Author(s):

J.G. Cohen ◽

R. Wiedemeyer ◽

B.Y. Karlan ◽

C. Walsh

Keyword(s):

Lynch Syndrome ◽

Microsatellite Instability ◽

Hot Spot ◽

Endometrial Carcinomas ◽

Mlh1 Methylation

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Microsatellite Instability and Epigenetic Inactivation of MLH1 and Outcome of Patients With Endometrial Carcinomas of the Endometrioid Type

Journal of Clinical Oncology ◽

10.1200/jco.2006.08.2107 ◽

2007 ◽

Vol 25 (15) ◽

pp. 2042-2048 ◽

Cited By ~ 134

Author(s):

Israel Zighelboim ◽

Paul J. Goodfellow ◽

Feng Gao ◽

Randall K. Gibb ◽

Matthew A. Powell ◽

...

Keyword(s):

Endometrial Cancer ◽

Microsatellite Instability ◽

Restriction Analysis ◽

Methylation Status ◽

Disease Free Survival ◽

Survival Outcomes ◽

Gynecology And Obstetrics ◽

Endometrial Carcinomas ◽

The Impact ◽

Mlh1 Methylation

Purpose Most studies of microsatellite instability (MSI) and outcomes in endometrial cancer patients have included varied histologic subtypes. Nonetheless, MSI occurs almost exclusively in endometrioid tumors. The impact of MSI on outcomes in patients with endometrial cancer is controversial. We sought to determine whether MSI and MLH1 methylation are associated with clinicopathologic variables and survival outcomes in a large series of patients with endometrial carcinomas of the endometrioid type. Patients and Methods Tumor samples, blood, and clinicopathologic data were prospectively collected and analyzed for 446 patients with endometrioid carcinomas. MSI was determined using five National Cancer Institute (NCI) consensus panel markers, and the methylation status of the MLH1 promoter was determined by combined bisulfite restriction analysis (COBRA). Associations with clinicopathologic variables and survival outcomes were evaluated. Results MSI was identified in 147 cases (33%). MSI was associated with higher International Federation of Gynecology and Obstetrics (FIGO) grade (P < .0001). MSI+ tumors without MLH1 methylation were associated with younger age (P < .001). MSI was not associated with overall survival (OS; hazard ratio [HR], 1.011; 95% CI, 0.688 to 1.484; P = .96) or disease-free survival (DFS; HR 0.951; 95% CI, 0.554 to 1.635; P = .86). The combined MSI/MLH1 methylation status (treating MSI− as the reference) did not predict OS (MSI+/MLH1-U: HR, 0.62; 95% CI, 0.27 to 1.44; P = .26; MSI+/MLH1-M: HR, 0.95; 95% CI, 0.62 to 1.46; P = .82) or DFS (MSI+/MLH1-U: HR, 0.51; 95% CI, 0.22 to 1.19; P = .12; MSI+/MLH1-M: HR, 0.93; 95% CI, 0.62 to 1.40; P = .72). Conclusion MSI is not associated with survival in patients with endometrioid endometrial cancer.

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