Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome

• DOI: 10.1016/j.gim.2022.02.016
• Publication Date: 2022-03-26T01:34:07Z
• Authors: Ying L. Liu; Karen A. Cadoo; Anna Maio; Zalak Patel; Yelena Kemel; Erin Salo-Mullen; Amanda Catchings; Megha Ranganathan; Sarah Kane; Robert Soslow; Ozge Ceyhan-Birsoy; Diana Mandelker; Maria I. Carlo; Michael F. Walsh; Jinru Shia; Arnold J. Markowitz; Kenneth Offit; Zsofia K. Stadler; Alicia Latham
• Keywords: Male; 0303 health sciences; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Endometrial Neoplasms; 3. Good health; DNA-Binding Proteins; 03 medical and health sciences; Humans; Female; Microsatellite Instability; Age of Onset; MutL Protein Homolog 1; Mismatch Repair Endonuclease PMS2

This study aimed to characterize MSH6/PMS2-associated mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) tumors, given revised guidelines suggesting more modest phenotypes.Patients who consented to Institutional Review Board-approved protocols of tumor/germline sequencing or Lynch syndrome registry at a single institution from February 2005 to January 2021 with germline, heterozygous MSH6/PMS2 pathogenic/likely pathogenic variants were identified. Clinical data were abstracted and correlated with MMR/microsatellite instability status using nonparametric tests.We identified 243 patients (133 sequencing, 110 registry) with germline MSH6/PMS2 pathogenic/likely pathogenic variants; 186 (77%) had >1 cancer. Of 261 pooled tumors, colorectal cancer (CRC) and endometrial cancer (EC) comprised 55% and 43% of cancers in MSH6 and PMS2, respectively; 192 tumors underwent molecular assessments and 122 (64%) were MMR-D/MSI-H (77 in MSH6, 45 in PMS2). MMR-D/MSI-H cancers included CRC (n = 56), EC (n = 35), small bowel cancer (n = 6), ovarian cancer (n = 6), urothelial cancer (n = 5), pancreas/biliary cancer (n = 4), gastric/esophageal cancer (n = 3), nonmelanoma skin tumors (n = 3), prostate cancer (n = 2), breast cancer (n = 1), and central nervous system/brain cancer (n = 1). Among MMR-D/MSI-H CRC and EC, median age of diagnosis was 51.5 (range = 27-80) and 55 (range = 39-74) years, respectively; 9 of 56 (16%) MMR-D/MSI-H CRCs were diagnosed at age <35 years.MSH6/PMS2 heterozygotes remain at risk for a broad spectrum of cancers, with 16% of MMR-D/MSI-H CRCs presenting before upper threshold of initiation of colonoscopy per guidelines.