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<p>Prostate cancer (PCa) is one of the most heritable common malignancies, yet data on germline genetic susceptibility in the Spanish population remain limited, and testing indications vary across guidelines. We aimed to characterize germline pathogenic variants (PVs) in Spanish PCa patients and identify predictors of carrier status. We retrospectively analyzed 360 PCa patients referred for genetic counseling. Multigene panel testing of 13 cancer predisposition genes was performed. PV frequencies were compared with internal pseudo-controls and public population controls. Associations with age at diagnosis, clinical risk group, and family history (FH) were evaluated. Overall, 6.4% of patients carried a germline PV. <i>BRCA2</i> and <i>ATM</i> were the most frequently mutated genes (1.67% each), showing significant enrichment compared with all control groups. <i>TP53</i> and <i>PALB2</i> were also significantly associated with PCa risk. High-risk or metastatic disease, age &lt; 60 years, and FH of hereditary breast/ovarian or Lynch syndrome-spectrum tumors were the best predictors for the presence of PV. Our findings suggest an unexpected major role for <i>TP53</i> and <i>PALB2</i> as key PCa susceptibility genes, reinforce the role of <i>BRCA2</i> and <i>ATM</i>, and question the role of <i>BRCA1</i>. Genetic testing may be most informative when focused on younger patients with non-low-risk disease and relevant FH.</p>

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Germline pathogenic variants associated with prostate cancer susceptibility in a Spanish cohort: emergence of new key players

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月2日

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  • Camila Reeb,
  • Graciela Uría-Regojo,
  • Jesús González-González,
  • Ana Amil,
  • Roberta Radu,
  • Yolanda Benítez,
  • Carmen Gomis,
  • Fiona Blanco-Kelly,
  • Andreea Mireia,
  • Fermina López-Grondona,
  • Isabel Lorda-Sánchez,
  • Elena Salgado,
  • Ana Isabel Sánchez-Barbero,
  • Saoud Swafiri,
  • Helena Gimbernat,
  • Daniel Ramírez-Martín,
  • Adrián Husillos-Alonso,
  • Miguel Sánchez-Encinas,
  • Carmen González-Enguita,
  • María José Trujillo,
  • Carmen Ayuso,
  • Pablo Mínguez,
  • Ana Osorio

摘要

Prostate cancer (PCa) is one of the most heritable common malignancies, yet data on germline genetic susceptibility in the Spanish population remain limited, and testing indications vary across guidelines. We aimed to characterize germline pathogenic variants (PVs) in Spanish PCa patients and identify predictors of carrier status. We retrospectively analyzed 360 PCa patients referred for genetic counseling. Multigene panel testing of 13 cancer predisposition genes was performed. PV frequencies were compared with internal pseudo-controls and public population controls. Associations with age at diagnosis, clinical risk group, and family history (FH) were evaluated. Overall, 6.4% of patients carried a germline PV. BRCA2 and ATM were the most frequently mutated genes (1.67% each), showing significant enrichment compared with all control groups. TP53 and PALB2 were also significantly associated with PCa risk. High-risk or metastatic disease, age < 60 years, and FH of hereditary breast/ovarian or Lynch syndrome-spectrum tumors were the best predictors for the presence of PV. Our findings suggest an unexpected major role for TP53 and PALB2 as key PCa susceptibility genes, reinforce the role of BRCA2 and ATM, and question the role of BRCA1. Genetic testing may be most informative when focused on younger patients with non-low-risk disease and relevant FH.