Early age of onset and broad cancer spectrum persist in <i>MSH6</i> and <i>PMS2</i>-associated Lynch syndrome.
Authors: Ying L Liu, Karen Anne Cadoo, Anna Maio, Zalak Patel, Yelena Kemel, Erin E. Salo-Mullen, Amanda Catchings, Megha Ranganathan, Sarah R. Kane, Jinru Shia, Robert A. Soslow, Ozge Birsoy, Diana Mandelker, Jaclyn Frances Hechtman, Maria Isabel Carlo, Michael Francis Walsh, Arnold Markowitz, Kenneth Offit, Zsofia Kinga Stadler, Alicia Latham
Journal: Journal of Clinical Oncology (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 &lt; 0.001 overall, p = 0.001 for MSH6, and p &lt; 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 &lt; 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.