Precision Oncology Insights into WNT Pathway Alterations in FOLFOX-Treated Early-Onset Colorectal Cancer in High-Risk Populations
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Background
Early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, is rising rapidly and disproportionately affects high-risk populations, including Hispanic/Latino (H/L) individuals. Although FOLFOX is a standard first-line chemotherapy for microsatellite stable (MSS) CRC, its efficacy and impact on tumor genomics in EOCRC remain understudied. Given the central role of WNT signaling in CRC pathogenesis, this study aimed to characterize WNT pathway alterations in EOCRC across diverse populations and assess their association with FOLFOX treatment and clinical outcomes.
Methods
We analyzed somatic mutation data from 2,515 CRC patients (266 H/L, 2,249 Non-Hispanic White [NHW]) from publicly available datasets. Patients were stratified by age (EOCRC vs. late-onset CRC [LOCRC]), ancestry (H/L vs. NHW), and FOLFOX treatment status. Mutation frequencies in WNT pathway genes were compared using chi-squared tests, and Kaplan-Meier analysis was used to assess overall survival.
Results
WNT pathway alterations were prevalent across all groups, with APC mutations dominating. Among H/L EOCRC patients, FOLFOX-treated individuals had significantly lower mutation rates in CTNNB1 (5.5% vs. 17.3%, p = 0.04) and RNF43 (5.5% vs. 19.2%, p = 0.02) compared to untreated counterparts. Similar patterns were observed between untreated EOCRC and LOCRC H/L patients for CTNNB1 (17.3% vs. 4.0%, p = 0.05) and RNF43 (19.2% vs. 10.0%, p = 0.006). In NHW LOCRC patients, FOLFOX treatment was associated with lower mutation frequencies in AXIN1 (2.0% vs. 4.6%, p = 0.004), AXIN2 (3.5% vs. 9.8%, p = 4.4×10⁻⁷), RNF43 (6.5% vs. 14.7%, p = 1.5×10⁻⁷), and TCF7L2 (13.1% vs. 18.1%, p = 0.008). Among NHW EOCRC patients, APC mutations were more frequent in untreated vs. treated groups (81.1% vs. 73.2%, p = 0.01), while AXIN2 and RNF43 mutations were less common. H/L EOCRC patients not treated with FOLFOX had significantly higher CTNNB1 (17.3% vs. 7.6%, p = 0.047) and RNF43 (19.2% vs. 6.6%, p = 0.006) mutation frequencies than their NHW counterparts. Kaplan-Meier analysis showed that WNT pathway alterations were associated with improved overall survival in FOLFOX-treated NHW EOCRC patients (p = 0.025) and in both treated (p = 0.02) and untreated (p = 0.015) NHW LOCRC patients. No significant survival differences were observed in H/L patients, though favorable trends were noted.
Conclusions
WNT pathway dysregulation is pervasive in EOCRC and varies by ancestry, treatment status, and age. FOLFOX chemotherapy appears to reduce the prevalence of specific non-canonical WNT alterations (e.g., CTNNB1, RNF43) in H/L EOCRC, while in NHW patients, broader WNT gene reductions were associated with improved survival. These findings suggest ancestry-specific molecular responses to chemotherapy and underscore the need for precision oncology approaches tailored to high-risk populations.
