Pathway-Specific Genomic Alterations in Pancreatic Cancer Across Populations at Risk

Pancreatic cancer (PC) is a highly aggressive malignancy with increasing incidence and poor survival. Hispanic/Latino (H/L) patients, despite having a lower overall incidence than Non-Hispanic White (NHW) patients, are often diagnosed younger and at more advanced stages, leading to worse outcomes. The molecular mechanisms underlying these disparities remain unclear. This study characterizes mutations in key oncogenic pathways-TP53, WNT, PI3K, TGF-Beta, and RTK/RAS-among H/L and NHW patients using publicly available datasets. We analyzed genomic data from 4248 PC patients (407 H/L; 3841 NHW), comparing mutation frequencies across pathways. Chi-squared tests assessed group differences, and Kaplan-Meier analysis evaluated survival outcomes by pathway alterations. TGF-Beta pathway mutations were less common in H/L patients (18.4% vs. 24.4%, <i>p</i> = 8.6 × 10^-3), with notable differences in <i>SMAD2</i> (1.5% vs. 0.4%, <i>p</i> = 6.3 × 10^-3) and <i>SMAD4</i> (15% vs. 19.9%, <i>p</i> = 0.02). While overall differences in other pathways were not statistically significant, several genes showed borderline significance, including <i>ERBB4, ALK, HRAS, RIT1</i> (RTK/RAS), and <i>CTNNB1</i> (WNT). No significant survival differences were observed in H/L patients, but NHW patients with TP53 alterations showed borderline survival associations. This study reveals ethnicity-specific pathway alterations in PC, with <i>SMAD2, ERBB4, ALK,</i> and <i>CTNNB1</i> mutations being more frequent in H/L patients, while <i>SMAD4</i> and <i>PI3K</i> alterations had prognostic value in NHW patients. These findings indicate the importance of incorporating ethnicity-specific molecular profiling into precision oncology for PC.