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

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.

Screening and testing practices for Lynch syndrome in Nova Scotians with endometrial cancer: a descriptive study

“…The patients’ demographic characteristics were similar to those of other populations of patients with endometrial cancer. 10 – 12 , 15 , 17 , 19 , 20 …”

“…The prevalence of Lynch syndrome in our population is similar to that in a previously described US population 15 , 16 but, interestingly, is less than half that reported in a cohort of Montréal patients. 17 At the time of writing, germline status remained unknown for 91 of the 189 participants eligible for genetic counselling. Our criteria for referral to medical genetics were broader than those in the studies by Hampel and colleagues 15 and Lawrence and colleagues.…”

Antioxidative, Anti-Inflammatory, Anti-Obesogenic, and Antidiabetic Properties of Tea Polyphenols—The Positive Impact of Regular Tea Consumption as an Element of Prophylaxis and Pharmacotherapy Support in Endometrial Cancer

“…The likelihood of EC in women suffering from Lynch syndrome is between 40 and 60% [ 31 ]. In another study conducted in Canada, it was reported that Lynch syndrome was diagnosed in 6.4% of EC patients over the age of 70 [ 32 ].…”

Genetic etiology of DNA-mismatch repair deficiency in cancer

“…Screening individuals for LS genetic testing based on clinical criteria was important as an inexpensive approach to detect patients at risk on a population scale. However, this screening method relies on accurate information about cancer prevalence in pedigrees to estimate their risk of being families with LS (LAWRENCE et al, 2021). Moreover, screening approaches based on clinical criteria were found to have low sensitivity, with half of CRC-associated LS cases being missed, which required new methods to identify suspected LS in the genetic testing .…”

“…In 2009, the American working group named Evaluation of Genomic Applications in Practice and Prevention (EGAPP) recommended screening all CRC for detecting LS (EGAPP, 2009). Currently, the universal use of tumor screening by either MSI or IHC for all newly diagnosed CRC and EC is highly recommended by several international institutions (DI MARCO et al, 2018;GIARDIELLO et al, 2014;JU et al, 2018;LAWRENCE et al, 2021;LEE et al, 2020;SYNGAL et al, 2015). In addition to CRC and EC, some authors also support universal screening in other LS-associated tumors, including ovarian, urinary, and sebaceous tumors (KUNNACKAL JOHN et al, 2022).…”