A study conducted by Dana-Farber Cancer Institute researchers found that germline cancer susceptibility mutations are more common in colorectal cancer (CRC) patients than thought previously (J Clin Oncol 2017; doi:10.1200/JCO.2016.71.0012). This discovery suggests that expanding genetic testing in CRC to more patients than just those at high risk for inherited conditions like Lynch Syndrome could offer them more opportunities for genetically driven cancer prevention. Indeed, “these data raise the provocative question of whether all patients with CRC should undergo multigene germline testing for inherited cancer susceptibility,” according to the authors.

The investigators conducted the study to determine the prevalence of cancer susceptibility gene mutations in a general population of CRC patients. Prior research mostly has looked at further cancer susceptibility in CRC patients with known high-risk features, such as early age at diagnosis or having tumors with microsatellite instability or DNA mismatch repair characteristics.

The current study included 1,058 CRC patients receiving clinic-based care who had not been preselected for high-risk features. All underwent germline testing for 25 mutations associated with inherited cancer risk. The researchers classified mutations as high- or moderate-penetrance based on published estimates of lifetime risk associated with the pathogenic mutations.

Overall, 9.9% of participants carried at least one pathogenic mutation, including 3.3% who had Lynch Syndrome mutations, a figure consistent with traditional estimates of Lynch Syndrome prevalence.  

Among the 6.6% of patients with pathogenic but not Lynch Syndrome-related mutations, most did not have clinical signs or symptoms that corresponded with their mutation status, and they also lacked typical phenotypic features of hereditary CRC risk, such as being younger than age 50 at diagnosis. Some of the more common high penetrance mutations included PALB2, CDKN2A, and TP53. About 1% of patients also harbored BRCA1/2 mutations, “substantially higher” than the estimated general population prevalence of 0.25%, raising questions about whether these mutations predispose to CRC, according to the authors.