Hypoxic CA9 variant as a potential prognostic marker in gastric and breast cancers

Gastric cancer (GC) and breast cancer (BC) are among the most common malignancies worldwide, with significant mortality rates despite advances in diagnosis and treatment. Genetic variants in the hypoxia-inducible factor (HIF) pathway, which plays an important role in tumor microenvironment adaptation, have emerged as potential contributors to cancer susceptibility and prognosis. Our study investigates the role of HIF pathway genetic variants in GC and BC among the Mizo population, an indigenous group living at high altitudes in north-eastern India. In addition, the EGLN1 c.12C > G (rs186996510) "Tibetan allele" was evaluated within this population-specific genetic framework. Whole-exome sequencing data from 74 cancer patients (59 GC, 15 BC) and 27 healthy controls were analyzed. Variants underwent quality filtering, in silico functional annotation, and association analyses including odds ratio (OR) and hazard ratio (HR) estimation. The EGLN1 Tibetan allele was prevalent in 29.62% of healthy Mizo controls and demonstrated a reduced association trend with GC (OR = 0.671) and BC (OR = 0.364). Common variants in CA9 (rs2071676), CDC20B (rs444527) and CDH11 (rs35195) showed associations for both cancers, with CA9 rs2071676 showing an association with poorer survival (HR = 4.097, p = 0.0139). Rare variants such as CA9 (rs77984049) and ABCB1 (rs2032582) also showed high ORs, particularly in GC. Overall, these findings provide exploratory, population-specific insight into HIF pathway genetic variation within a high-altitude indigenous population and contribute to the understanding of population-based cancer associations. Further investigation in larger cohorts with comprehensive clinical modeling and functional validation is warranted.