Racial/Ethnic and Sex Differences in Somatic Cancer Gene Mutations among Patients with Early-Onset Colorectal Cancer

Area of Science:

• Oncology
• Genomics
• Cancer Disparities

Background:

• Colorectal cancer (CRC) disparities persist, with underlying molecular features often uncharacterized.
• Understanding genomic variations across different racial/ethnic groups and sexes is crucial for addressing these disparities, particularly in early-onset cases.

Purpose of the Study:

• To investigate somatic mutation patterns in early-onset colorectal cancer by race/ethnicity and sex.
• To identify specific genes and molecular pathways contributing to observed disparities in colorectal cancer.

Main Methods:

• Analysis of somatic mutation data from 5,856 non-Hispanic white (NHW), 535 non-Hispanic Black (NHB), and 512 Asian/Pacific Islander (API) patients.
• Comparison of mutation frequencies and rates in early-onset (age <50) and late-onset colorectal cancer, stratified by race/ethnicity and sex.

Main Results:

• NHB patients with early-onset nonhypermutated CRC exhibited higher tumor mutation rates than NHW patients.
• Significant differences in mutation frequencies for genes including LRP1B, FLT4, FBXW7, RNF43, ATRX, APC, and PIK3CA were found between racial/ethnic groups in early-onset nonhypermutated CRC.
• Sex-based heterogeneity was observed for mutations in EP300, BRAF, WRN, KRAS, AXIN2, and SMAD2, with distinct age-related trends in EP300 mutations between males and females.

Conclusions:

• Genomic patterns of early-onset nonhypermutated colorectal cancer vary significantly by race/ethnicity and sex.
• These findings provide novel biological insights into the molecular drivers of early-onset colorectal cancer disparities.
• Identifying these molecular differences can inform targeted therapeutic strategies and early detection efforts.