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<p>Tumoral <i>BRCA1</i> promoter methylation occurs frequently in triple-negative breast cancer (TNBC) and contributes to homologous recombination deficiency (HRD). While constitutional <i>BRCA1</i> methylation has been described, its relationship with tumoral methylation, genomic instability, and prognosis remains unclear. Paired tumor and blood samples from 136 TNBC patients (SCANDARE, NCT03017573) were analyzed for BRC<i>A1</i> methylation, genomic alterations, HRD and outcomes. Constitutional <i>BRCA1</i> methylation was detected in 20.6% of patients and tumoral methylation in 31.6%, including 11.5% with somatic-only methylation. In cases with constitutional <i>BRCA1</i> methylation, tumoral methylation levels increased markedly, with 89% of high-methylation tumors (≥50%) associated with a Loss of Heterozygoty. Tumors with <i>BRCA1</i> promoter methylation consistently exhibited high HRD (Homologous Recombination Deficiency) scores, comparable to those with pathogenic HRR (Homologous Recombination Repair) gene pathogenic variants (p &lt; 0.001). Conversely, HRD was rare in tumors lacking both <i>BRCA1</i> methylation and HRR gene alterations. Prognostically, constitutional BRCA1 methylation tended to associate with improved survival, while somatic-only methylation showed a trend toward poorer outcomes (p = 0.06). Constitutional <i>BRCA1</i> methylation is associated with a high level of tumoral <i>BRCA1</i> promoter methylation and HRD in TNBC. These findings support integrating constitutional and tumoral <i>BRCA1</i> methylation into HRD assessment to improve patient stratification and precision treatment in TNBC.</p>

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Constitutional BRCA1 Methylation is associated with high level of tumoral BRCA1 methylation and homologous recombination deficiency in triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • Justine Pasanisi,
  • Constance Lamy,
  • Lolita Lecompte,
  • Sophie Vacher,
  • Mathias Schwartz,
  • Abderaouf Hamza,
  • Sandrine M. Caputo,
  • Sabrina Ibadioune,
  • Laura Courtois,
  • Frédérique Berger,
  • Vincent Cockenpot,
  • Sylvain Baulande,
  • Jean-Yves Pierga,
  • Celine Callens,
  • Samia Melaabi,
  • Chrystelle Colas,
  • Eric Pasmant,
  • Maud Kamal,
  • Célia Dupain,
  • Nicolas Servant,
  • Christophe Le Tourneau,
  • Ivan Bièche

摘要

Tumoral BRCA1 promoter methylation occurs frequently in triple-negative breast cancer (TNBC) and contributes to homologous recombination deficiency (HRD). While constitutional BRCA1 methylation has been described, its relationship with tumoral methylation, genomic instability, and prognosis remains unclear. Paired tumor and blood samples from 136 TNBC patients (SCANDARE, NCT03017573) were analyzed for BRCA1 methylation, genomic alterations, HRD and outcomes. Constitutional BRCA1 methylation was detected in 20.6% of patients and tumoral methylation in 31.6%, including 11.5% with somatic-only methylation. In cases with constitutional BRCA1 methylation, tumoral methylation levels increased markedly, with 89% of high-methylation tumors (≥50%) associated with a Loss of Heterozygoty. Tumors with BRCA1 promoter methylation consistently exhibited high HRD (Homologous Recombination Deficiency) scores, comparable to those with pathogenic HRR (Homologous Recombination Repair) gene pathogenic variants (p < 0.001). Conversely, HRD was rare in tumors lacking both BRCA1 methylation and HRR gene alterations. Prognostically, constitutional BRCA1 methylation tended to associate with improved survival, while somatic-only methylation showed a trend toward poorer outcomes (p = 0.06). Constitutional BRCA1 methylation is associated with a high level of tumoral BRCA1 promoter methylation and HRD in TNBC. These findings support integrating constitutional and tumoral BRCA1 methylation into HRD assessment to improve patient stratification and precision treatment in TNBC.