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Molecular features underlying colorectal cancer disparities remain uncharacterized. Here, we investigated somatic mutation patterns by race/ethnicity and sex among 5,856 non-Hispanic white (NHW), 535 non-Hispanic Black (NHB), and 512 Asian/Pacific Islander (API) patients with colorectal cancer (2,016 early-onset colorectal cancer patients: sequencing age Significance:NHBs, but not APIs, with early-onset nonhypermutated colorectal cancer had higher adjusted tumor mutation rates versus NHWs. Differences for FLT4, FBXW7, RNF43, LRP1B, APC, PIK3CA, and ATRX mutation rates between racial/ethnic groups and EP300, KRAS, AXIN2, WRN, BRAF, and LRP1B mutation rates by sex were observed in tumors of young patients.See related commentary by Shen et al., p. 530 .This article is highlighted in the In This Issue feature, p. 517

Table S1. Clinical and demographic characteristics of the colorectal cancer (CRC) patient study population by race/ethnicity and age at sequencing: AACR Project GENIE.Table S2. Baseline mutation probability, comparison and heterogeneity of non-silent somatic gene mutations among patients with early-onset and late-onset nonhypermutated colorectal cancer. Genes ranked by false discovery rate (FDR).Table S3. Racial/ethnic patterns in baseline mutation probability, comparison and heterogeneity of all non-silent somatic gene mutations among patients with early-onset and late-onset non-hypermutated colorectal cancer.Table S4. Baseline mutation probability, comparison and heterogeneity of non-silent somatic gene mutations among patients with earlyonset and late-onset non-hypermutated colorectal cancer by sex.Table S5. Read depth for clinical-grade targeting sequencing data from tumor tissues and case counts by early-onset and late-onset groups and sequencing center. Figure S1. Mutation rates among 6,903 tumor samples from colorectal cancer patients across racial/ethnic groups.Figure S2. Adjusted mutation rates in 653 hypermutated colorectal tumors: AACR GENIE.Figure S3. Tumor mutational burden (TMB) across sequencing assay/platform for early-onset and late-onset non-hypermutated colorectal cancer cases: AACR Project GENIE.Figure S4. Frequency of non-silent somatic mutations in commonly assayed and mutated genes between early-onset and late-onset non-hypermutated CRC cases (mutation frequency >10%).

Molecular features underlying colorectal cancer disparities remain uncharacterized. Here, we investigated somatic mutation patterns by race/ethnicity and sex among 5,856 non-Hispanic white (NHW), 535 non-Hispanic Black (NHB), and 512 Asian/Pacific Islander (API) patients with colorectal cancer (2,016 early-onset colorectal cancer patients: sequencing age LRP1B, FLT4, FBXW7, RNF43, ATRX, APC, and PIK3CA mutation frequencies in early-onset nonhypermutated colorectal cancers between racial/ethnic groups. Heterogeneities by race/ethnicity were observed for the effect of APC, FLT4, and FAT1 between early-onset and late-onset nonhypermutated colorectal cancer. By sex, heterogeneity was observed for the effect of EP300, BRAF, WRN, KRAS, AXIN2, and SMAD2. Males and females with nonhypermutated colorectal cancer had different trends in EP300 mutations by age group. These findings define genomic patterns of early-onset nonhypermutated colorectal cancer by race/ethnicity and sex, which yields novel biological clues into early-onset colorectal cancer disparities.Significance:NHBs, but not APIs, with early-onset nonhypermutated colorectal cancer had higher adjusted tumor mutation rates versus NHWs. Differences for FLT4, FBXW7, RNF43, LRP1B, APC, PIK3CA, and ATRX mutation rates between racial/ethnic groups and EP300, KRAS, AXIN2, WRN, BRAF, and LRP1B mutation rates by sex were observed in tumors of young patients.See related commentary by Shen et al., p. 530.This article is highlighted in the In This Issue feature, p. 517