Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome. Academic Article uri icon

Overview

abstract

  • PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

authors

  • Liu, Ying
  • Cadoo, Karen A
  • Maio, Anna
  • Patel, Zalak
  • Kemel, Yelena
  • Salo-Mullen, Erin
  • Catchings, Amanda
  • Ranganathan, Megha
  • Kane, Sarah
  • Soslow, Robert
  • Ceyhan-Birsoy, Ozge
  • Mandelker, Diana
  • Carlo, Maria I
  • Walsh, Michael F
  • Shia, Jinru
  • Markowitz, Arnold J
  • Offit, Kenneth
  • Stadler, Zsofia K
  • Latham, Alicia

publication date

  • March 26, 2022

Research

keywords

  • Colorectal Neoplasms, Hereditary Nonpolyposis
  • DNA-Binding Proteins
  • Endometrial Neoplasms

Identity

PubMed Central ID

  • PMC9942243

Scopus Document Identifier

  • 85127305434

Digital Object Identifier (DOI)

  • 10.1097/AOG.0000000000004676

PubMed ID

  • 35346574

Additional Document Info

volume

  • 24

issue

  • 6