Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer

The early-onset colorectal cancer (EOCRC) burden differs across racial/ethnic groups, yet the role of germline genetic predisposition in EOCRC disparities remains uncharacterized. We defined the prevalence and spectrum of inherited colorectal cancer (CRC) susceptibility gene variations among patients with EOCRC by race and ethnicity. We included individuals diagnosed with a first primary CRC between age 15 and 49 years who identified as Ashkenazi Jewish, Asian, Black, Hispanic, or White and underwent germline genetic testing of 14 CRC susceptibility genes performed by a clinical testing laboratory. Variant comparisons by racial and ethnic groups were evaluated using chi-square tests and multivariable logistic regression adjusted for sex, age, CRC site, and number of primary colorectal tumors. Among 3,980 patients with EOCRC, a total of 530 germline pathogenic or likely pathogenic variants were identified in 485 individuals (12.2%). By race/ethnicity, 12.7% of Ashkenazim patients, 9.5% of Asian patients, 10.3% of Black patients, 14.0% of Hispanic patients, and 12.4% of White patients carried a germline variant. The prevalence of Lynch syndrome ( = .037), as well as , , , monoallelic , and variants, varied by race/ethnicity among patients with EOCRC (all < .026). Ashkenazim and Hispanic patients had significantly higher odds of presenting with a pathogenic variant, which included p.I1307K (odds ratio [OR], 2.67; 95% CI, 1.30 to 5.49; = .007) and variant (OR, 8.69; 95% CI, 2.68 to 28.20; = .0003), respectively, versus White patients in adjusted models. Germline genetic features differed by race/ethnicity in young patients with CRC, suggesting that current multigene panel tests may not be representative of EOCRC risk in diverse populations. Further study is needed to optimize genes selected for genetic testing in EOCRC via ancestry-specific gene and variant discovery to yield equitable clinical benefits for all patients and to mitigate inequities in disease burden.