Molecular insights into HER2/ERBB2 amplification and carcinogenesis in gallbladder cancer associated with pancreaticobiliary maljunction

TL;DR

This study explores how a genetic change called HER2/ERBB2 amplification contributes to gallbladder cancer in patients with a condition called pancreaticobiliary maljunction.

Contribution

The study is the first to evaluate HER2/ERBB2 expression in gallbladder cancer with pancreaticobiliary maljunction using multiple advanced techniques.

Findings

ERBB2 amplification was detected in 50% of gallbladder cancer patients with pancreaticobiliary maljunction.

HER2 protein expression was significantly higher in gallbladder cancer with pancreaticobiliary maljunction compared to other groups.

The study highlights a potential molecular link between gallbladder cancer and pancreaticobiliary maljunction that could guide targeted therapies.

Abstract

Pancreaticobiliary maljunction (PBM) contributes to epithelial hyperplasia and, ultimately, the development of gallbladder cancer (GBC). Despite its clinical significance, the molecular and cellular mechanisms driving carcinogenesis in GBC with PBM remain poorly elucidated. This study investigated the oncogenic mechanisms, biomarkers, and performance associated with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeted therapies in GBC with PBM.

Overall, 127 surgically treated patients were stratified as follows: Group A, normal gallbladder; Group B, PBM; Group C, GBC without PBM; and Group D, GBC with PBM. We performed whole-exome sequencing (WES) for Group D and human epidermal growth factor receptor 2 immunohistochemistry (HercepTest) for the entire cohort. Fluorescence in situ hybridization (FISH) was used to clarify human epidermal growth factor receptor 2 (HER2) expression in cases with equivocal HercepTest results.

ERBB2 amplification was detected in 50% of Group D patients. The proportion of HER2 protein expression scores ≥ 2 + was highest in Group D compared with that in the other groups (50.0% vs. 0% in Groups A and B and 15.6% in Group C) (P = 0.006, chi-squared test). Finally, 37.5% and 13.3% of cases in Groups D and C, respectively, showed HER2 overexpression (P = 0.037, chi-squared test).

This is the first evaluation of HER2/ERBB2 expression in GBC with PBM based on WES, HercepTest, and FISH. The significant increase in ERBB2 expression, driven by the synergistic interplay between GBC and PBM, underscores a critical molecular interaction that may inform the development of targeted therapeutic strategies.

The online version contains supplementary material available at 10.1007/s00535-025-02303-2.

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