Genetic Testing in Colorectal Cancer

Abstract

C olorectal cancer (CRC) constitutes a significant global health challenge, ranking as the second leading cause of cancer-related mortality worldwide. 1 In 2023, the Surveillance, Epidemiology, and End Results (SEER) estimated 153,020 new CRC cases and 52,550 deaths in the United States. 2 Despite a 2% yearly decrease in CRC mortality from 2011 to 2020, individuals under 50 experienced a 0.5% to 3% rise each year. 3 Remarkably, 13% of new CRC cases in 2023 were expected to occur under the age of 50, with 43% of these between 45 and 49 years old. 3 A 2024 report from the American Cancer Society highlights that CRC will move from the fourth to the leading cause of cancer death in men and second in women under 50 within 2 decades. 4 Moreover, young-onset patients are often diagnosed at advanced stages, with regional and distant-stage diagnoses increasing by about 3% yearly, compared with a 1% annual decrease in localized disease from 2010 to 2019. 3 Oncogenetics investigates the relationship between genetic DNA variants and cancer development. It underscores genetics as a major CRC risk, with a heredity component contributing to roughly 35% of cases. 5 Lynch syndrome accounts for 3% of the CRC cases in the United States, making it the most prevalent cause of the 5% of CRCs due to hereditary CRC syndrome. 6 Genetic polyposis syndromes like familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome (PJS), and juvenile polyposis syndrome (JPS) significantly raise the risk of polyps and can increase CRC risk. A retrospective cohort study provided compelling evidence on the high prevalence of genetic mutations: 1 in 279 of the population carry mutations in mismatch repair (MMR) genes (MLH1 = 1 in 1946, MSH2 = 1 in 2841, MSH6 = 1 in 758, and PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of CRC in unidentified major genes. 7 Historically, CRC genetic testing has relied on immunohistochemical (IHC) of MMR protein expression or microsatellite instability (MSI) testing to screen for LS probands. However, about 7% of CRC patients screened for germline mutations, regardless of age, family history, or MSI/MMR status, carry pathogenic germline variants (PGVs) linked to hereditary cancer syndromes other than LS. 6 Following this, the National Comprehensive Cancer Network (NCCN) updated its "Genetic/Familial High-Risk Assessment: Colorectal" guidelines, offering recommendations on hereditary CRC syndrome management, including multigene panel testing (MGPT). 8 This review addresses the latest MGPT advancements for CRC, offering expert recommendations and stressing the importance of strategic genetic testing in patient care.