Decoding WNT Pathway Dysregulation in Bevacizumab-Treated Early-Onset Colorectal Cancer to Inform Precision Oncology

Early-onset colorectal cancer (EOCRC) is rising most rapidly among Hispanic/Latino (H/L) populations, yet the prognostic relevance of WNT pathway alterations under contemporary therapies remains unclear. We conducted a multi-cohort analysis integrating somatic genomics with clinical and treatment annotations (including bevacizumab exposure) from public CRC datasets, stratifying by age of onset and ancestry (H/L vs. non-Hispanic White [NHW]). WNT alterations, dominated by APC, were ubiquitous, but their distribution and outcome associations were context dependent. Across several strata, bevacizumab exposure was associated with lower observed mutation frequencies in select WNT genes (notably RNF43, AXIN1/2, TCF7L2, AMER1), consistent with biological interplay or treatment-related selection. Prognostically, WNT alterations predicted improved overall survival in H/L EOCRC and in NHW late-onset CRC (LOCRC), but worse survival in NHW EOCRC. These findings nominate WNT pathway context as a candidate biomarker for disparity-aware risk stratification in EOCRC and motivate mechanistic studies of anti-angiogenic WNT interactions. Prospective, multi-institutional validation incorporating treatment timing, tumor microenvironment, and social context is warranted to translate these signals into equitable precision oncology.