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Background <p>Patients with clinical characteristics of increased cancer susceptibility without an identified genetic lesion are regularly seen in clinics. Association studies and matched normal/tumour sequencing have advanced the discovery of Cancer Susceptibility Genes (CSGs), with limitations when used independently. We reasoned that combining these strategies alongside mutational signatures and clinical data could improve CSGs identification.</p> Methods <p>Using breast and ovarian cancer exome data from The Cancer Genome Atlas (TCGA-BRCA and TCGA-OV), we developed a genomic framework that evaluates exome-wide associations of Germline Pathogenic Variants (GPVs) harbouring second hits with Homologous Recombination Repair Deficiency (HRD) mutational signatures (HRDSig) to identify novel HRD-related CSGs. This is complemented by clinico-genomic analysis evaluating clinical and biological plausibility.</p> Results <p>Our framework confirmed significant associations with HRDSig of <i>BRCA1/2</i> GPVs with second hits in both TCGA cohorts, validating its performance. <i>THBS4</i> also reached significance but only&#xa0;co-occurred with other HRD-related events in TCGA-BRCA. Borderline significance was also observed for <i>KIF13B</i> and <i>TESPA1</i>, also&#xa0;only in TCGA-BRCA. The clinico-genomics approach further identified <i>KIF13B</i> and <i>TESPA1</i>, as well as <i>RAD51B</i> and other Fanconi Anaemia pathway-related genes, including <i>FANCD2</i>, warranting further validation.</p> Conclusions <p>Our&#xa0;approach provides a framework for the identification of candidate HRD-related CSGs through combined statistical and clinico-genomics analyses. It is adaptable to other mutational signatures/cancer types and will be most effective when applied to larger and well-annotated datasets.</p>

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A comprehensive genomic framework for identifying genes predisposing to homologous recombination repair-deficient breast or ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月8日

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  • José Camacho-Valenzuela,
  • Thibaut Matis,
  • Carla Roca,
  • Jorge Luis Cuamatzi Flores,
  • Nancy Hamel,
  • Barbara Rivera,
  • Simon Gravel,
  • Paz Polak,
  • Carla Daniela Robles-Espinoza,
  • William D. Foulkes

摘要

Background

Patients with clinical characteristics of increased cancer susceptibility without an identified genetic lesion are regularly seen in clinics. Association studies and matched normal/tumour sequencing have advanced the discovery of Cancer Susceptibility Genes (CSGs), with limitations when used independently. We reasoned that combining these strategies alongside mutational signatures and clinical data could improve CSGs identification.

Methods

Using breast and ovarian cancer exome data from The Cancer Genome Atlas (TCGA-BRCA and TCGA-OV), we developed a genomic framework that evaluates exome-wide associations of Germline Pathogenic Variants (GPVs) harbouring second hits with Homologous Recombination Repair Deficiency (HRD) mutational signatures (HRDSig) to identify novel HRD-related CSGs. This is complemented by clinico-genomic analysis evaluating clinical and biological plausibility.

Results

Our framework confirmed significant associations with HRDSig of BRCA1/2 GPVs with second hits in both TCGA cohorts, validating its performance. THBS4 also reached significance but only co-occurred with other HRD-related events in TCGA-BRCA. Borderline significance was also observed for KIF13B and TESPA1, also only in TCGA-BRCA. The clinico-genomics approach further identified KIF13B and TESPA1, as well as RAD51B and other Fanconi Anaemia pathway-related genes, including FANCD2, warranting further validation.

Conclusions

Our approach provides a framework for the identification of candidate HRD-related CSGs through combined statistical and clinico-genomics analyses. It is adaptable to other mutational signatures/cancer types and will be most effective when applied to larger and well-annotated datasets.