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Background <p>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 (<i>ERBB2)</i>-targeted therapies in GBC with PBM.</p> Methods <p>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.</p> Results <p><i>ERBB2</i> 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) (<i>P</i> = 0.006, chi-squared test). Finally, 37.5% and 13.3% of cases in Groups D and C, respectively, showed HER2 overexpression (<i>P</i> = 0.037, chi-squared test).</p> Conclusions <p>This is the first evaluation of HER2/<i>ERBB2</i> expression in GBC with PBM based on WES, HercepTest, and FISH. The significant increase in <i>ERBB2</i> expression, driven by the synergistic interplay between GBC and PBM, underscores a critical molecular interaction that may inform the development of targeted therapeutic strategies.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月4日

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  • Ming Zhu,
  • Daisuke Douchi,
  • Keigo Murakami,
  • Taito Itoh,
  • Shusuke Migita,
  • Naoki Rikiyama,
  • Shuichiro Hayashi,
  • Takashi Kokumai,
  • Hideaki Sato,
  • Shingo Yoshimachi,
  • Akiko Kusaka,
  • Mitsuhiro Shimura,
  • Shun Nakayama,
  • Shuichi Aoki,
  • Masahiro Iseki,
  • Takayuki Miura,
  • Shimpei Maeda,
  • Masaharu Ishida,
  • Hideo Ohtsuka,
  • Masamichi Mizuma,
  • Kei Nakagawa,
  • Atsushi Masamune,
  • Toru Furukawa,
  • Michiaki Unno

摘要

Background

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.

Methods

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.

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).

Conclusions

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.