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

BACKGROUND AND PURPOSE:

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