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Background <p>Familial pancreatic cancer (FPC) will be enriched for germline mutations (GLMs), particularly in homologous recombination repair (HRR) genes, but its distinction from sporadic pancreatic cancer (PC) remains unclear.</p> Methods <p>We retrospectively analyzed 111 resected PCs, including 13 patients with FPC (11.8%) and 98 with non-FPC (88.2%). Whole-exome sequencing targeted 151 cancer-related genes, with parallel gene expression profiling. GLMs were assessed by ClinVar and in silico tools. Homologous recombination deficiency (HRD) scores, COSMIC signatures, immune deconvolution, and survival were compared.</p> Results <p>Patients with FPC and non-FPC were comparable in age, sex, tumor stage, and receipt of adjuvant chemotherapy. ClinVar-annotated GLMs were found in 2/13 patients with FPC (15.4%) and 4/98 patients with non-FPC (4.1%). FPC cases more often carried pancreatitis-associated variants (<i>SPINK1</i>, <i>CFTR</i>), whereas non-FPC included HRR-related variants (<i>PALB2</i>, <i>FANCG</i>). When potentially pathogenic HRR-related variants were considered together, prevalence was similar (23.1% vs. 12.2%, <i>p</i> = 0.380). HRD scores did not differ (median 22 vs. 19, <i>p</i> = 0.591), and high HRD scores (≥ 42) were observed only in two non-FPC cases, including one with <i>PALB2</i>. Differential expression analysis revealed no significant differences after false discovery rate correction. Multivariate analysis indicated that FPC status was not an independent prognostic factor (hazard ratio 1.73, <i>p</i> = 0.084).</p> Conclusions <p>Transcriptomic profiles and HRD status were similar between patients with FPC and patients with non-FPC. A spectrum of GLMs was observed in both groups, suggesting that hereditary risk variants are not exclusive to FPC and underscoring the importance of germline testing in all patients with PC.</p>

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Comparison of Familial and Sporadic Pancreatic Cancer: Clinicopathological and Genomic Features

  • 期刊论文

  • 发表日期：

    2025年10月14日

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  • Yuya Miura,
  • Sumiko Ohnami,
  • Keiichi Ohshima,
  • Takeshi Nagashima,
  • Yukiyasu Okamura,
  • Keiichi Hatakeyama,
  • Kenichi Urakami,
  • Yasuto Akiyama,
  • Ryo Ashida,
  • Katsuhisa Ohgi,
  • Yoshiyasu Kato,
  • Shimpei Otsuka,
  • Hideyuki Dei,
  • Katsuhiko Uesaka,
  • Ken Yamaguchi,
  • Teiichi Sugiura

摘要

Background

Familial pancreatic cancer (FPC) will be enriched for germline mutations (GLMs), particularly in homologous recombination repair (HRR) genes, but its distinction from sporadic pancreatic cancer (PC) remains unclear.

Methods

We retrospectively analyzed 111 resected PCs, including 13 patients with FPC (11.8%) and 98 with non-FPC (88.2%). Whole-exome sequencing targeted 151 cancer-related genes, with parallel gene expression profiling. GLMs were assessed by ClinVar and in silico tools. Homologous recombination deficiency (HRD) scores, COSMIC signatures, immune deconvolution, and survival were compared.

Results

Patients with FPC and non-FPC were comparable in age, sex, tumor stage, and receipt of adjuvant chemotherapy. ClinVar-annotated GLMs were found in 2/13 patients with FPC (15.4%) and 4/98 patients with non-FPC (4.1%). FPC cases more often carried pancreatitis-associated variants (SPINK1, CFTR), whereas non-FPC included HRR-related variants (PALB2, FANCG). When potentially pathogenic HRR-related variants were considered together, prevalence was similar (23.1% vs. 12.2%, p = 0.380). HRD scores did not differ (median 22 vs. 19, p = 0.591), and high HRD scores (≥ 42) were observed only in two non-FPC cases, including one with PALB2. Differential expression analysis revealed no significant differences after false discovery rate correction. Multivariate analysis indicated that FPC status was not an independent prognostic factor (hazard ratio 1.73, p = 0.084).

Conclusions

Transcriptomic profiles and HRD status were similar between patients with FPC and patients with non-FPC. A spectrum of GLMs was observed in both groups, suggesting that hereditary risk variants are not exclusive to FPC and underscoring the importance of germline testing in all patients with PC.