Germline Genetic Testing in CRC: Implications for Familial and Population-Based Testing

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Scientific advances in DNA sequencing technologies have allowed for the simultaneous testing of multiple genes associated with an inherited susceptibility of CRC. As a result, CRC screening and treatment protocols have been affected by results from germline multigene panel testing,^1,2 including but not limited to Lynch syndrome (LS), the most common inherited CRC syndrome, which is associated with mismatch repair deficiency and tumor microsatellite instability.³

A demographic of concern for which systematic genetic risk assessment is recommended is the early-onset (EO) population—people diagnosed with CRC before age 50 years. More than 15% of EO-CRC cases are due to pathogenic variants in cancer susceptibility genes^3,4 irrespective of family cancer history, most of which are LS–related and most frequently detected as age at CRC diagnosis decreases.⁵ Thus, multiple international guidelines recommend that all individuals diagnosed with EO-CRC undergo germline genetic testing⁶; these results have implications for at-risk relatives, particularly when a familial pathogenic variant is detected and specialized cancer screening or risk-reducing strategies can be pursued in family members, many of whom are cancer-free. The alarming increase in EO-CRC rates has led to a focus on the assessment of familial and inherited CRC risk to optimize screening recommendations among the general population.^7,8

Furthermore, universal germline testing of all individuals with CRC is cost-effective and provides optimal surveillance for cancer survivors while also increasing the pool of at-risk, cancer-free relatives who benefi most from cancer screening and prevention protocols.⁹ In fact, indications for universal germline testing for relatives of individuals with CRC to personalize screening recommendations also supports future consideration for population-based germline genetic testing for LS genes, as the prevalence of the condition is 1 in 279 individuals, with more than 1 million individuals in the United States affected but unaware of their diagnosis.^10,11

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