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What Percentage of Individuals under 50 Years of Age with Colon Cancer Have Mutations Associated with Heritable Cancer?


  • 1/10 new colorectal cancers (CRC) diagnoses involves individuals <50 years
  • Lynch syndrome is associated with mutations in MMR genes and underlies 2-3% of CRC (see Lynch syndrome synopsis in ‘Related ObG Topics, below)
  • Familial Adenomatous Polyposis (FAP) is associated with mutations in the APC tumor suppressor gene and underlies 1% of CRCs
  • Current genetic sequencing is dependent on meeting specific clinical criteria
    • Age <50 years is an indication for referral but not necessarily genetic sequencing
  • Stoffel et al. (Gastroenterology, 2017) sought to determine what proportion of individuals < 50 years with CRC are carriers for mutations in genes associated with heritable cancer syndromes such as Lynch syndrome


  • Retrospective chart review study
  • Subjects: Individuals <50 years of age diagnosed with CRC
  • Data collection included patient histories, tumor phenotypes, and germline DNA sequencing
  • For subjects with uninformative evaluations because they did not undergo clinical germline DNA sequencing or clinical sequencing failed to identify a pathogenic germline mutation in the clinical genetics laboratory, germline DNA samples were sequenced using a research-based next-generation sequencing multigene panel
  • Primary outcome: Identification of a pathogenic germline mutation associated with cancer predisposition


  • 430 CRC individuals <50 years were evaluated
  • 111 (26%) had a first degree relative with CRC
  • 41 (10%) had tumors with histological evidence for mismatch repair deficiency consistent with MMR
  • Of 315 subjects who underwent sequencing, 79 had mutations associated with hereditary cancer syndrome and 21 had variants of uncertain significance
    • 56 subjects had pathogenic variants associated with Lynch syndrome
      • 25 with mutations in MSH2
      • 24 with mutations in MLH1
      • 5 with mutations in MSH6
      • 2 with mutations in PMS2
    • 10 subjects had pathogenic variants associated with FAP
  • Thirteen subjects had mutations in other cancer-associated genes (8 in MUTYH, 2 in SMAD4, 1 in BRCA1, 1 in TP53, and 1 in CHEK2)
  • 117 patients had uninformative clinical evaluations
    • DNA sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%)
  • Only 43 of the 85 subjects with germline mutations associated with a hereditary cancer syndrome (51%) reported a CRC diagnosis in a first degree relative


  • Approximately 1 in 5 young individuals diagnosed with CRC carries a germline mutation associated with cancer
  • Almost half of these patients did not have clinical histories typically associated with the identified syndrome
  • Germline testing with multigene cancer panels should be considered for all young patients with CRC

Learn More – Primary Sources:

Germline Genetic Features of Young Individuals with Colorectal Cancer