Mismatch Repair Universal Screening of Endometrial Cancers (MUSE) in a Canadian Cohort.

Jessica Lawrence,Laura Palma,Jocelyne Arseneau,Evan Weber,William Foulkes,Lara Richer,George Chong,Xing Zeng

doi:10.3390/curroncol28010052

Jessica Lawrence, Laura Palma + Show 6 more

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https://doi.org/10.3390/curroncol28010052

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Abstract

Background: Approximately 2–6% of endometrial cancers (ECs) are due to Lynch Syndrome (LS), a cancer predisposition syndrome caused by germline pathogenic variants (PVs) affecting the DNA mismatch repair (MMR) pathway. Increasingly, universal tissue-based screening of ECs has been proposed as an efficient and cost-effective way to identify families with LS, though few studies have been published on Canadian cohorts. The purpose of this study was to evaluate the feasibility and overall performance of a universal immunohistochemistry (IHC) screening program for women with EC within a single Canadian university hospital centre. Methods and Results: From 1 October 2015 to 31 December 2017, all newly diagnosed ECs (n = 261) at our centre were screened for MMR protein deficiency by IHC. MMR deficiency was noted in 69 tumours (26.4%), among which 53 had somatic MLH1 promoter hypermethylation and were considered “screen-negative”. The remaining MMR-deficient cases (n = 16) were considered “screen-positive” and were referred for genetic counselling and testing. Germline PVs were identified in 12/16 (75%). One additional PV was identified in a screen-negative individual who was independently referred to the Genetics service. This corresponds to an overall LS frequency of 5.0% among unselected women with EC, and 6.4% among women diagnosed under age 70 years. Our algorithm detected MMR gene pathogenic variants in 4.6% and 6.2% of unselected individuals and individuals under age 70 years, respectively. Four germline PVs (30.8%) were identified in individuals who did not meet any traditional LS screening criteria. Conclusions: Universal IHC screening for women with EC is an effective and feasible method of identifying individuals with LS in a Canadian context.

Highlights

2–6% of endometrial cancers (ECs) are due to Lynch Syndrome (LS), a cancer predisposition syndrome caused by germline pathogenic variants (PVs) affecting the DNA mismatch repair (MMR) pathway
Heterozygous germline PVs resulting in deficient production of the MLH1, MSH2, MSH6, and/or PMS2 proteins leads to LS15 as well as truncating terminal deletions of the EPCAM gene, which cause inactivation of the MSH2 gene by hypermethylation of its promoter region [16]
This population could be considered for universal IHC screening programs in the future, though inclusion of all endometrial intraepithelial neoplasia (EIN) in this study would have likely decreased the efficiency of the screen, requiring more tumours to be screened for every germline PV identified

Summary

Introduction

2–6% of endometrial cancers (ECs) are due to Lynch Syndrome (LS), a cancer predisposition syndrome caused by germline pathogenic variants (PVs) affecting the DNA mismatch repair (MMR) pathway. One additional PV was identified in a screen-negative individual who was independently referred to the Genetics service This corresponds to an overall LS frequency of 5.0% among unselected women with EC, and 6.4% among women diagnosed under age 70 years. LS is caused by germline PVs in any one of five genes: MLH1, MSH2, MSH6, PMS2, and EPCAM [15] These genes each have an effect on the DNA mismatch repair (MMR) pathway which identifies and corrects errors in the DNA sequence generated during DNA replication [15]. Heterozygous germline PVs resulting in deficient production of the MLH1, MSH2, MSH6, and/or PMS2 proteins leads to LS15 as well as truncating terminal deletions of the EPCAM gene, which cause inactivation of the MSH2 gene by hypermethylation of its promoter region [16]

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