Background/Objectives: Early-onset colorectal cancer (EOCRC; diagnosed before age 50) is rising at an accelerated rate, with a disproportionate impact on underserved populations. While alterations in the receptor tyrosine kinase–RAS (RTK–RAS) signaling pathway play a fundamental role in colorectal cancer (CRC) biology, their prognostic significance in the setting of FOLFOX chemotherapy—particularly across different age groups and ancestral backgrounds—remains insufficiently characterized. We sought to characterize age-, ancestry-, and treatment-specific associations between RTK–RAS alterations and clinical outcomes using an AI-enabled precision oncology framework. Methods: We analyzed 2515 CRC cases, including 266 Hispanic/Latino (H/L) and 2249 non-Hispanic White (NHW) patients, stratified by age at onset, ancestry, and FOLFOX treatment status. Mutation frequencies were assessed using Fisher’s exact and chi-square tests, while overall survival was analyzed with Kaplan–Meier methods. The AI-HOPE and AI-HOPE–RTK–RAS conversational artificial intelligence platforms were used to integrate clinical, genomic, and treatment data via multi-parameter, natural language–based queries. Results: In early-onset Hispanic/Latino patients, ERBB2 and NF1 mutations occurred at significantly lower frequencies in FOLFOX-treated cases compared with untreated cases (p= 0.01 for both). In late-onset H/L patients, NTRK2 mutations were depleted in FOLFOX-treated tumors (p= 0.04). In untreated early-onset H/L patients, MAPK3 and NF1 mutations were enriched relative to NHW counterparts. Among early-onset NHW patients, IGF1R and ERRFI1 mutations were less frequent with FOLFOX exposure, while multiple RTK–RAS genes were reduced in FOLFOX-treated late-onset NHW patients. Survival analyses revealed worse overall survival in FOLFOX-untreated early-onset NHW patients with RTK–RAS alterations (p= 0.029), but improved survival in FOLFOX-treated late-onset NHW patients (p= 0.048). Conclusions: RTK–RAS pathway alterations demonstrate strong age-, ancestry-, and treatment-specific prognostic effects and may serve as precision biomarkers of differential chemotherapy response. AI-enabled analytics substantially accelerated integrative biomarker discovery, supporting their utility for advancing precision oncology in EOCRC.
背景/目的：早发性结直肠癌（EOCRC；诊断年龄小于50岁）正以前所未有的速度增长，并对医疗服务不足的人群造成尤为严重的影响。尽管受体酪氨酸激酶–RAS（RTK–RAS）信号通路的改变在结直肠癌（CRC）的生物学机制中起着基础性作用，但其在FOLFOX化疗方案中的预后意义——特别是在不同年龄组和不同祖先背景的患者中——仍未得到充分阐明。本研究旨在利用人工智能赋能的精准肿瘤学框架，揭示RTK–RAS改变与临床结局之间与年龄、祖先背景及治疗特异性相关的关联。方法：我们分析了2515例结直肠癌病例，包括266例西班牙裔/拉丁裔（H/L）患者和2249例非西班牙裔白人（NHW）患者，并按发病年龄、祖先背景及FOLFOX治疗状态进行分层。使用Fisher精确检验和卡方检验评估突变频率，并使用Kaplan–Meier方法分析总生存期。通过AI-HOPE和AI-HOPE–RTK–RAS对话式人工智能平台，整合临床、基因组和治疗数据，进行基于自然语言的多参数查询。结果：在接受FOLFOX治疗的早发性西班牙裔/拉丁裔患者中，ERBB2和NF1突变的发生频率显著低于未治疗患者（两者p=0.01）。在晚发性H/L患者中，NTRK2突变在接受FOLFOX治疗的肿瘤中显著减少（p=0.04）。在未接受治疗的早发性H/L患者中，MAPK3和NF1突变的发生率高于非西班牙裔白人早发性患者。在早发性NHW患者中，IGF1R和ERRFI1突变在接受FOLFOX治疗后频率降低；而在晚发性NHW患者中，多个RTK–RAS基因在接受FOLFOX治疗后表达减少。生存分析显示，在伴有RTK–RAS改变的未接受FOLFOX治疗的早发性NHW患者中，总生存期更差（p=0.029），但在接受FOLFOX治疗的晚发性NHW患者中生存期有所改善（p=0.048）。结论：RTK–RAS通路改变显示出强烈的年龄、祖先背景及治疗特异性预后效应，并可能作为个体化化疗反应的精准生物标志物。人工智能辅助分析显著加速了整合性生物标志物的发现，支持其在推动EOCRC精准肿瘤学发展中的应用价值。
肿瘤(癌症)患者之家