The H63D Polymorphism in the HFE Gene Promotes Aggressive Disease Phenotypes in Pancreatic Ductal Adenocarcinoma.

Abstract

Controversy exists regarding the association between HFE H63D polymorphism and pancreatic ductal adenocarcinoma (PDAC). This study initially assessed the frequency of H63D in PDAC patients and subsequently investigated correlations between genotype and disease phenotype. H63D prevalence was determined by genotyping 795 PDAC patients from two retrospective cohorts of unselected (n = 389) or surgically resected (n = 171) individuals, and one prospective cohort of resectable cases (n = 235). Associations between H63D status and clinicopathological variables were retrospectively evaluated in unselected patients and prospectively validated in surgical candidates. The phenotypic impact of H63D carriage was also investigated using a genetically engineered KCH67D murine model and PDAC cell lines. Spatial transcriptomics was applied to human PDAC samples to define genotype-associated microenvironmental and cell-cycle alterations. H63D prevalence was higher in patients with resectable PDAC (37.7%, 37.4%, and 34% across cohorts) than in those with unresectable disease (22.4%) or the general population (24.1%). Despite this, resected H63D carriers had significantly worse outcomes, with the variant emerging as an independent predictor of shorter disease-free survival (p = 0.002). Consequently, KCh67d mice developed earlier, larger tumors with increased metastatic spread. H63D PDAC cells and tumor spatial transcriptomic showed enhanced invasiveness, G1-phase accumulation, and TGFβ-independent EMT activation. The H63D variant is strongly associated with PDAC resectability and, paradoxically, with a poorer post-surgical outcome. Activation of a TWIST1-dependent EMT program within a G1-enriched cellular context underlies the more aggressive phenotype of H63D PDAC, possibly accounting for the clinical conundrum.