Dataset Information

Identification of novel Lynch syndrome mutations in Chinese patients with endometriod endometrial cancer.

ABSTRACT: Objective: Lynch syndrome (LS) predisposes patients to early onset endometrioid endometrial cancer (EEC). However, little is known about LS-related EEC in the Chinese population. The aim of this study was to investigate the prevalence of LS and to identify the specific variants of LS in Chinese patients with EEC. Methods: We applied universal immunohistochemistry screening to detect the expression of mismatch repair (MMR) proteins, which was followed by MLH1 methylation analysis to identify suspected LS cases, next-generation sequencing (NGS) to confirm LS, and microsatellite instability (MSI) analysis to verify LS. Results: We collected 211 samples with EEC. Twenty-seven (27/211, 12.8%) EEC cases had a loss of MMR protein expression. After MLH1 methylation analysis, 16 EEC cases were suggested to be associated with LS. Finally, through NGS and MSI analysis, we determined that 10 EEC (10/209, 4.78%) cases were associated with LS. Among those cases, 3 unreported mutations (1 frameshift and 2 nonsense) were identified. MSH6 c.597_597delC, found in 4 patients, is likely to be a founder mutation in China. Conclusions: We demonstrated the feasibility of a process for LS screening in Chinese patients with EEC, by using universal immunohistochemistry screening followed by MLH1 methylation analysis and confirmation through NGS and MSI analysis. The novel mutations identified in this study expand knowledge of LS.

SUBMITTER: Ren C

PROVIDER: S-EPMC7309470 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Identification of novel Lynch syndrome mutations in Chinese patients with endometriod endometrial cancer.

Ren Caixia C Liu Yan Y Wang Yuxiang Y Tang Yan Y Wei Yawei Y Liu Congrong C Zhang Hongquan H

Cancer biology & medicine 20200501 2

<b>Objective:</b> Lynch syndrome (LS) predisposes patients to early onset endometrioid endometrial cancer (EEC). However, little is known about LS-related EEC in the Chinese population. The aim of this study was to investigate the prevalence of LS and to identify the specific variants of LS in Chinese patients with EEC. <b>Methods:</b> We applied universal immunohistochemistry screening to detect the expression of mismatch repair (MMR) proteins, which was followed by MLH1 methylation analysis to ...[more]

PMID: 32587781

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Project description:ContextLynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear.ObjectiveTo establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands.Design, setting, and patientsPooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data.Main outcomePerformance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening).ResultsOf 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach.ConclusionUniversal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.

Project description:Background & aimsMultigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome.MethodsWe performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients' personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing.ResultsOf the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%-90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%-10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%-7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%).ConclusionsIn individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients' histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS.

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Dataset Information

Identification of novel Lynch syndrome mutations in Chinese patients with endometriod endometrial cancer.

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Identification of novel Lynch syndrome mutations in Chinese patients with endometriod endometrial cancer.

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