Early age of onset and broad cancer spectrum persist in MSH6 and PMS2-associated Lynch syndrome.
Authors: Liu Ying L , Cadoo Karen Anne , Maio Anna , Patel Zalak , Kemel Yelena , Salo-Mullen Erin E. , Catchings Amanda , Ranganathan Megha , Kane Sarah R. , Shia Jinru , Soslow Robert A. , Birsoy Ozge , Mandelker Diana , Hechtman Jaclyn Frances , Carlo Maria Isabel , Walsh Michael Francis , Markowitz Arnold , Offit Kenneth , Stadler Zsofia Kinga , Latham Alicia 
Published: June 2021

10516

Background: Recently updated NCCN guidelines for management of germline MSH6 and PMS2 pathogenic/likely pathogenic (P/LP) variant carriers suggest a more modest phenotype with later onset colorectal cancer (CRC) and limited extra-colonic cancers compared to other Lynch Syndrome (LS) genes. However, data are limited, and a comprehensive understanding of the risk spectrum and age of cancer onset is critical for cancer screening and risk-reduction. We sought to characterize MSH6 and PMS2-associated cancers and age of diagnosis in those with mismatch repair deficient (MMRD)/ microsatellite instability-high (MSI-H) tumors, a hallmark of LS pan-cancer. Methods: Pts consented to IRB-approved protocols of tumor/germline sequencing or to a prospective registry of LS pts at a single institution from 2/2005-01/2021 were reviewed to identify those with germline heterozygous MSH6/ PMS2 P/LP variants; pts with constitutional MMRD (CMMRD) were excluded. In cancer-affected pts, tumors were evaluated for MSI and/or MMR protein expression via immunohistochemistry. Tumor types were tabulated, and clinical variables were correlated with MMR/MSI status using non-parametric tests. Results: We identified 243 pts (159 female, 94 male) with P/LP germline MSH6/PMS2 variants, and 186 (77%) pts had a confirmed cancer [ MSH6 111/148 (75%); PMS2 75/95 (79%)]. Overall, 51 (21%) pts had multiple primary cancers, 35 (24%) in MSH6 and 16 (17%) in PMS2 (p = 0.20), resulting in 261 total tumors, 160 in MSH6 and 101 in PMS2. Of the 191 tumors with molecular assessment, 118 (62%) were MMRD/MSI-H, including CRC (n = 54), endometrial (EC, n = 34), small bowel (SBA, n = 6), ovarian (OC, n = 5), urothelial (n = 5), pancreato-biliary (n = 4), gastroesophageal (n = 3), non-melanoma skin (n = 3), prostate (n = 2), breast (n = 1), and brain (n = 1). While CRC and EC were more likely to be MMRD/MSI-H (79% each) compared to other cancers (37%) (p < 0.001 overall, p = 0.001 for MSH6, and p < 0.001 for PMS2), 25% of all MMRD/MSI-H tumors in both genes were comprised of non-CRC/EC cancers. Notably, there were 6 SBAs (5 in PMS2, 1 in MSH6), and all were MMRD/MSI-H. There were 17 OCs (12 in PMS2, 5 in MSH6), and of the 12 that underwent molecular assessment, 5 (41.7%) were MMRD/MSI-H (3 PMS2, 2 MSH6). Among MMRD/MSI-H CRC and EC, median age of diagnosis was 51.5 (range 27-80) and 55 (range 39-74) respectively, with 9/54 (17%) of CRC (4 in MSH6, 5 in PMS2) diagnosed < age 35, the suggested upper threshold for initiation of colonoscopy per NCCN. Conclusions: Despite being lower penetrance LS-associated genes, pts with MSH6/PMS2 P/LP variants remain at risk for a broad-spectrum of cancers and very early-onset CRC, with 17% of MMRD/MSI-H CRC presenting prior to upper threshold of initiation of colonoscopic screening per NCCN.