Survey of germline variants in cancer-associated genes in young adults with colorectal cancer

Genes Chromosomes Cancer. 2022 Feb;61(2):105-113. doi: 10.1002/gcc.23011. Epub 2021 Nov 18.


Colorectal cancer (CRC) incidence in young adults is rising. Identifying genetic risk factors is fundamental for the clinical management of patients and their families. This study aimed to identify clinically significant germline variants among young adults with CRC. Whole-exome sequencing data of blood-derived DNA from 133 unrelated young CRC patients (<55 years of age) underwent a comprehensive analysis of 133 cancer-predisposition/implicated genes. All patient tumors were evaluated for mismatch repair deficiency (dMMR). Among 133 patients (aged 16-54 years), 15% (20/133) had clinically actionable pathogenic or likely pathogenic (P/LP) variants in at least 1 well established cancer-predisposing gene: dMMR genes (6), MUTYH [bi-allelic (2), mono-allelic (3)], RNF43 (1), BMPR1A (1), BRCA2 (4), ATM (1), RAD51C (1), and BRIP1 (1). Five patients (4%) had variants in genes implicated in cancer but where the significance of germline variants in CRC risk is uncertain: GATA2 (1), ERCC2 (mono-allelic) (1), ERCC4 (mono-allelic) (1), CFTR (2). Fourteen (11%) had dMMR tumors. Eighteen (14%) reported a first-degree relative with CRC, but only three of these carried P/LP variants. Three patients with variants in polyposis-associated genes showed no polyposis (one each in MUTYH [bi-allelic], RNF43, and BMPR1A). Approximately one in five young adults in our series carried at least one P/LP variant in a cancer-predisposing/implicated gene; 80% of these variants are currently considered clinically actionable in a familial cancer setting. Family history and phenotype have limitations for genetic risk prediction; therefore multigene panel testing and genetic counseling are warranted for all young adults with CRC regardless of those two factors.

Keywords: BRCA2; mismatch repair; whole-exome sequencing; young-onset CRC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Biomarkers, Tumor / genetics*
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / genetics
  • Colorectal Neoplasms* / diagnosis
  • Colorectal Neoplasms* / epidemiology
  • Colorectal Neoplasms* / genetics
  • DNA Mismatch Repair / genetics
  • Exome Sequencing
  • Female
  • Germ-Line Mutation / genetics*
  • Humans
  • Male
  • Middle Aged
  • Neoplastic Syndromes, Hereditary / diagnosis
  • Neoplastic Syndromes, Hereditary / genetics
  • Young Adult


  • Biomarkers, Tumor

Supplementary concepts

  • Turcot syndrome