Background: Colorectal cancer (CRC) demonstrates substantial clinical and biological diversity across age groups, ancestral backgrounds, and treatment settings, alongside a rising incidence of early-onset disease (EOCRC). The mitogen-activated protein kinase (MAPK) pathway is a major driver of CRC development and therapy response; however, the distribution and prognostic value of MAPK alterations across distinct patient subgroups remain unclear. Methods: We analyzed 2515 CRC tumors with harmonized demographic, clinical, genomic, and treatment metadata. Patients were stratified by ancestry (Hispanic/Latino [H/L] vs. non-Hispanic White [NHW]), age at diagnosis (early-onset [EO] vs. late-onset [LO]), and FOLFOX chemotherapy exposure. MAPK pathway alterations were identified using a curated gene set encompassing canonical EGFR-RAS-RAF-MEK-ERK signaling components and regulatory nodes. Conversational artificial intelligence (AI-HOPE and AI-HOPE-MAPK) enabled natural language-driven cohort construction and exploratory analytics; findings were validated using Fisher’s exact testing, chi-square analyses, and Kaplan–Meier survival estimates. Results: MAPK pathway disruption demonstrated marked heterogeneity across ancestry and treatment contexts. Among EO H/L patients,FGFR3, NF1, and RPS6KA6mutations were significantly enriched in tumors not receiving FOLFOX, whereasPDGFRBalterations were more frequent in FOLFOX-treated EO H/L tumors relative to EO NHW counterparts. In late-onset H/L disease,NTRK2andPDGFRBmutations were more common in non-FOLFOX tumors. Distinct MAPK-associated alterations were also observed among NHW patients, particularly in non-FOLFOX settings, includingAKT3, FGF4, RRAS2, CRKL, DUSP4, JUN, MAPK1, RRAS,andSOS1. Survival analyses provided borderline evidence that MAPK alterations may be linked to improved overall survival in treated EO NHW patients. Conversational AI markedly accelerated analytic throughput and multi-parameter discovery. Conclusions: Although MAPK alterations are pervasive in CRC, their distribution varies meaningfully by ancestry, age, and treatment exposure. These findings highlightNF1, MAPK3, RPS6KA4, andPDGFRBas potential biomarkers in EOCRC and H/L patients, supporting the need for ancestry-aware precision oncology approaches.
背景：结直肠癌（CRC）在不同年龄组、种族背景和治疗环境中表现出显著的临床和生物学异质性，同时早发性结直肠癌（EOCRC）的发病率不断上升。丝裂原活化蛋白激酶（MAPK）通路是CRC发生发展和治疗反应的主要驱动因素；然而，MAPK通路改变在不同患者亚组中的分布及其预后价值尚不明确。方法：我们分析了2515例结直肠癌肿瘤样本，并整合了人口统计学、临床、基因组和治疗相关元数据。根据种族（西班牙裔/拉丁裔[H/L] vs. 非西班牙裔白人[NHW]）、诊断年龄（早发性[EO] vs. 晚发性[LO]）以及FOLFOX化疗暴露情况对患者进行分层。通过一个经过筛选的基因集识别MAPK通路改变，该基因集涵盖经典的EGFR-RAS-RAF-MEK-ERK信号通路成分及调控节点。采用对话式人工智能（AI-HOPE和AI-HOPE-MAPK）实现自然语言驱动的队列构建和探索性分析；研究结果通过Fisher精确检验、卡方分析和Kaplan–Meier生存估计进行验证。结果：MAPK通路改变在种族和治疗背景下表现出显著异质性。在未接受FOLFOX治疗的EO H/L患者肿瘤中，FGFR3、NF1和RPS6KA6突变显著富集；而相较于EO NHW患者，接受FOLFOX治疗的EO H/L患者肿瘤中PDGFRB改变更为常见。在晚发性H/L患者中，NTRK2和PDGFRB突变在未接受FOLFOX治疗的肿瘤中更常见。在NHW患者中也观察到独特的MAPK相关改变，特别是在非FOLFOX治疗背景下，包括AKT3、FGF4、RRAS2、CRKL、DUSP4、JUN、MAPK1、RRAS和SOS1。生存分析提供了临界证据，表明在接受治疗的EO NHW患者中，MAPK改变可能与总生存期改善相关。对话式人工智能显著加快了分析速度和多参数发现。结论：尽管MAPK改变在CRC中普遍存在，但其分布因种族、年龄和治疗暴露情况的不同而存在显著差异。这些发现提示NF1、MAPK3、RPS6KA4和PDGFRB可能作为EOCRC和H/L患者的潜在生物标志物，支持了在精准肿瘤学中考虑种族差异的必要性。
肿瘤(癌症)患者之家