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Background <p>Germline pathogenic variants in <i>BRCA1/2</i> and mismatch repair (MMR) genes have distinct therapeutic implications. However, concurrent germline variants involving both pathways are rarely reported in gallbladder cancer, making identification of the dominant tumor biology critical for treatment selection.</p> Case presentation <p>A 73-year-old woman presented with advanced gallbladder cancer and a significant family history of malignancy. Biopsy revealed poorly differentiated adenocarcinoma with focal squamous cell differentiation. Comprehensive genomic profiling identified germline pathogenic variants in <i>BRCA2</i> and <i>PMS2</i>, alongside a high tumor mutational burden (18.2 mutations/Mb). The elevated tumor mutational burden and the observed mutational profile were consistent with mismatch repair deficiency; subsequent immunohistochemistry confirmed loss of <i>PMS2</i> expression in tumor cells. Conversely, <i>BRCA2</i> loss of heterozygosity was not detected; our assessment of BRCA-related involvement was limited to LOH because HRD scoring was not available from the clinical CGP. Based on an MMR-deficient phenotype, the patient received gemcitabine/cisplatin plus pembrolizumab, achieving a partial response maintained for 8&#xa0;months. Post-test genetic counseling was provided, and cascade testing was offered to at-risk relatives; however, no relatives have undergone testing to date because consent could not be obtained.</p> Conclusion <p>This case illustrates that integrating comprehensive genomic profiling with mutational signature analysis and immunohistochemistry can clarify the dominant driver process and guide immunotherapy-based treatment selection in gallbladder cancer.</p>

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Gallbladder cancer with dual genetic variants of PMS2 and BRCA2: a case report

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Ryohei Sumii,
  • Shizuma Omote,
  • Rika Omote,
  • Isao Fujita,
  • Tatsuya Toyokawa

摘要

Background

Germline pathogenic variants in BRCA1/2 and mismatch repair (MMR) genes have distinct therapeutic implications. However, concurrent germline variants involving both pathways are rarely reported in gallbladder cancer, making identification of the dominant tumor biology critical for treatment selection.

Case presentation

A 73-year-old woman presented with advanced gallbladder cancer and a significant family history of malignancy. Biopsy revealed poorly differentiated adenocarcinoma with focal squamous cell differentiation. Comprehensive genomic profiling identified germline pathogenic variants in BRCA2 and PMS2, alongside a high tumor mutational burden (18.2 mutations/Mb). The elevated tumor mutational burden and the observed mutational profile were consistent with mismatch repair deficiency; subsequent immunohistochemistry confirmed loss of PMS2 expression in tumor cells. Conversely, BRCA2 loss of heterozygosity was not detected; our assessment of BRCA-related involvement was limited to LOH because HRD scoring was not available from the clinical CGP. Based on an MMR-deficient phenotype, the patient received gemcitabine/cisplatin plus pembrolizumab, achieving a partial response maintained for 8 months. Post-test genetic counseling was provided, and cascade testing was offered to at-risk relatives; however, no relatives have undergone testing to date because consent could not be obtained.

Conclusion

This case illustrates that integrating comprehensive genomic profiling with mutational signature analysis and immunohistochemistry can clarify the dominant driver process and guide immunotherapy-based treatment selection in gallbladder cancer.