Colorectal cancer incidence among individuals age younger than 50 (early-onset CRC) continues to rise with etiologies unknown. Synchronously, early-onset CRC disparities have grown more pronounced. Molecular characteristics underlying CRC disparities among young adults remain uncharacterized. In a study of 5,292 patients (1,483 early-onset; 28.0%) with CRC and clinical-grade targeted sequencing data from AACR Project GENIE, we explored tumor mutational burden (TMB) and genomic patterns of early-onset CRC by race/ethnicity using multivariable regression models adjusted for sex, histology, sequencing assay, primary sample type and TMB. In total, 9.4% of CRCs (n=500) were hypermutated (>17.77 mutations/Mb). Excluding the hypermutated cancers, early-onset CRCs had 5.6 mutations/Mb versus 6.2 mutations/Mb among CRCs from late-onset cases. Moreover, among young patients, Blacks (n=115), but not Asians (n=122), had significantly higher TMB compared with Whites (n=1,245) with non-hypermutated CRC (P=0.02 and 0.38, respectively). Overall, young patients with non-hypermutated CRCs had significantly higher odds of presenting with nonsilent mutations in TP53 (Odds Ratio [OR]=1.26, 95%CI: 1.08-1.47, P=0.003) and SMAD2 (OR=1.69, 95%CI: 1.19-2.40, P=0.003) versus late-onset cases after adjustment for sex, race, histology, sequencing assay, sample type and TMB. In contrast, young patients had a 40% and 44% decreased odds of presenting with KDR and FLT4 nonsilent mutations, respectively, compared with patients with late-onset non-hypermutated CRC (KDR: OR=0.60, 95%CI: 0.38-0.95, P=0.03; FLT4: OR=0.56, 95%CI: 0.33-0.94, P=0.03). Mutation heterogeneity in TGFBR2 (Cochran's Q test: P=0.003) and NOTCH1 (P=0.02) was also observed between early-onset and late-onset cases. By race, distinct genomic patterns of early-onset CRC emerged. Young Whites with non-hypermutated CRC had higher odds of presenting with SMAD2 and TP53 mutations (SMAD2: OR=1.88, 95%CI:1.28-2.78, P=0.001; TP53: OR=1.25, 95%CI:1.06-1.48, P=0.007), and decreased odds of presenting with FLT4 mutations (OR=0.56, 95%CI: 0.32-0.99, P=0.04) versus late-onset non-hypermutated CRC cases. Among Black individuals, early-onset non-hypermutated CRC cases had significantly higher odds of presenting with TGFBR2 nonsilent mutations versus late-onset cases (OR=61.37, 95%CI:2.24-1680.45, P=0.01). Young Asians had 6-fold increased odds of presenting with nonsilent mutations in NOTCH1 versus Asians with non-hypermutated late-onset CRC (OR=6.26, 95%CI:1.32-29.68, P=0.02). By race, distinct TGFBR2 (P=0.0001) and NOTCH1 (P=0.02) mutation frequencies were observed in non-hypermutated CRCs among young patients. Together, this study provides initial evidence that molecular features of early-onset CRC may differ by race/ethnicity, which could provide insight into biological mechanisms underlying early-onset CRC disparities.

Citation Format: Andreana N. Holowatyj, Wanqing Wen, Timothy Gibbs, Kay M. Washington, Paulette D. Chandler, Cathy Eng, Jose Perea, Wei Zheng, Xingyi Guo. Racial differences in somatic mutations among patients with early-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 101.