Background/Objectives: Early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, is rising rapidly and disproportionately affects Hispanic/Latino (H/L) populations. While FOLFOX is a standard first-line chemotherapy, its impact on tumor genomics in EOCRC remains poorly understood. Given the central role of WNT signaling in colorectal cancer (CRC), we aimed to characterize WNT pathway alterations in EOCRC across diverse populations and assess their associations with FOLFOX treatment and clinical outcomes. Methods: Somatic mutation data from 2515 CRC patients (266 H/L, 2249 Non-Hispanic White [NHW]) were analyzed. Patients were stratified by age (EOCRC vs. late-onset colorectal cancer), ancestry (H/L vs. NHW), and FOLFOX treatment status. Mutation frequencies in WNT pathway genes were compared, and Kaplan–Meier analysis evaluated overall survival. Results: WNT pathway alterations were pervasive across groups, with APC mutations dominating. Notably, non-canonical WNT mutations (e.g., CTNNB1, RNF43) were significantly less frequent in FOLFOX-treated H/L EOCRC patients compared to untreated individuals, suggesting potential chemotherapy-driven selection. In NHW patients, FOLFOX treatment was associated with reduced mutation frequencies across multiple WNT regulators, which correlated with improved overall survival. Conclusions: Our findings reveal that WNT pathway dysregulation in EOCRC is shaped by ancestry, treatment status, and age. FOLFOX appears to reduce specific WNT alterations in H/L patients and broader WNT disruptions in NHW patients, with survival benefits observed primarily in the latter. These results underscore ancestry-specific molecular responses to chemotherapy and the need for precision oncology strategies tailored to high-risk populations.
背景/目的：早发性结直肠癌（EOCRC）指诊断年龄在50岁以下的结直肠癌，其发病率正快速上升，且对西班牙裔/拉丁裔人群的影响尤为显著。尽管FOLFOX方案是标准一线化疗方案，但其对EOCRC肿瘤基因组的影响尚不明确。鉴于WNT信号通路在结直肠癌中的核心作用，本研究旨在系统描述不同人群EOCRC中WNT通路基因变异特征，并评估其与FOLFOX治疗及临床结局的关联。方法：分析2515例结直肠癌患者（含266例西班牙裔/拉丁裔及2249例非西班牙裔白人）的体细胞突变数据。根据年龄（EOCRC与晚发性结直肠癌）、族裔背景（西班牙裔/拉丁裔与非西班牙裔白人）及FOLFOX治疗状态进行分层，比较WNT通路基因突变频率，并通过Kaplan-Meier法评估总生存期。结果：WNT通路变异在各组中普遍存在，以APC突变为主。值得注意的是，在FOLFOX治疗的西班牙裔/拉丁裔EOCRC患者中，非经典WNT通路突变（如CTNNB1、RNF43）频率显著低于未治疗者，提示化疗可能驱动了选择性压力。在非西班牙裔白人患者中，FOLFOX治疗与多个WNT调控基因突变频率降低相关，且这种降低与总生存期改善存在关联。结论：本研究发现EOCRC中WNT通路失调受族裔背景、治疗状态及年龄共同影响。FOLFOX治疗可能减少西班牙裔/拉丁裔患者的特定WNT变异，并在非西班牙裔白人患者中更广泛地改善WNT通路异常，且生存获益主要见于后者。这些结果揭示了化疗反应的族裔特异性分子机制，强调需针对高危人群制定精准肿瘤学策略。
肿瘤(癌症)患者之家