Artificial Intelligence-Guided Molecular Determinants of PI3K Pathway Alterations in Early-Onset Colorectal Cancer Among High-Risk Groups Receiving FOLFOX
Abstract
Background
Early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, is rising rapidly and disproportionately affects high-risk populations, particularly Hispanic/Latino (H/L) individuals, who experience the steepest increases in incidence and mortality. While prevention and screening strategies have curbed late-onset CRC rates, EOCRC remains outside standard screening guidelines and is projected to become the leading cause of cancer-related death in individuals aged 20–49 by 2030. FOLFOX (folinic acid, fluorouracil, and oxaliplatin) is a standard first-line therapy for microsatellite stable (MSS) CRC lacking actionable driver mutations; however, its efficacy and genomic impact in EOCRC, particularly in underrepresented groups, remain poorly understood. The phosphatidylinositol 3-kinase (PI3K) pathway regulates cell growth, survival, and metabolism, and its alterations have been implicated in therapeutic resistance and adverse outcomes. Yet, the prevalence, clinical relevance, and treatment-specific associations of PI3K pathway alterations in EOCRC remain underexplored.
Methods
We analyzed somatic mutation and clinical data from 2,515 CRC patients (266 H/L and 2,249 Non-Hispanic White [NHW]) across publicly available genomic datasets. Patients were stratified by age at diagnosis (EOCRC <50 vs. LOCRC ≥50), ancestry (H/L vs. NHW), and FOLFOX treatment status. PI3K pathway alterations—including mutations in PIK3CA, PTEN, AKT isoforms, and regulatory genes—were identified using curated pathway definitions. Mutation prevalence was compared across groups using Fisher’s exact or chi-squared tests. AI-HOPE-PI3K, a conversational AI platform, was deployed to automate cohort construction, stratify subgroups, and perform post-hoc survival analysis.
Results
PI3K pathway alterations were observed across all demographic groups. In EO NHW patients treated with FOLFOX, Kaplan–Meier analysis revealed significantly reduced overall survival among those with PI3K pathway alterations (n = 124) compared with unaltered counterparts (n = 251; p = 0.0008), identifying alterations as a candidate prognostic biomarker in this subgroup. AI-guided subgroup interrogation further highlighted mutation-specific signals: INPP4B and RPTOR emerged as exploratory candidates in EO H/L patients but did not show significant treatment- or ancestry-specific enrichment upon confirmatory testing. Similarly, ancestry-stratified analysis of PIK3R2 mutations revealed comparable rates in EO H/L (1.37%) and EO NHW (1.6%) FOLFOX-treated patients (p = 1.0). Across ancestry and age groups, mutational landscape analysis revealed diverse molecular events—including missense, nonsense, splice-site, frameshift, and in-frame deletions—underscoring the heterogeneity of PI3K pathway dysregulation.
Conclusions
This study identifies PI3K pathway alterations as a potential prognostic marker of poor survival in EO NHW patients receiving FOLFOX and uncovers ancestry- and treatment-specific mutational differences in high-risk CRC populations. By integrating clinical, molecular, and treatment variables, the AI-HOPE and AI-HOPE-PI3K platforms enabled rapid, reproducible, and fine-grained analysis of complex datasets. These findings underscore the need for ancestry-informed molecular profiling to optimize therapeutic strategies and highlight AI-guided interrogation as a powerful tool for advancing precision oncology in underrepresented and disproportionately affected CRC populations.
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