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<p>Between 5 and 8% of the general population carry a constitutional methylation of the <i>BRCA1</i> promoter (“epimutation”). Several studies have suggested that these <i>BRCA1</i> epimutations confer an increased risk of breast cancer, in particular triple-negative breast cancer (TNBC), with an earlier onset than in the general population. However, those studies relied on very few patients with early-onset TNBC. Using specific Methylation-Sensitive High-Resolution Melting, we assessed <i>BRCA1</i> epimutation prevalence in a large cohort of 112 early-onset (≤ 30&#xa0;years-old) TNBC patients with no genetic&#xa0;cancer-predisposing pathogenic variants (PVs). We compared this cohort to 87 early-onset TNBC patients carrying cancer-predisposing PVs and to 93 late-onset (≥ 70&#xa0;years-old) TNBC with no cancer-predisposing PVs. We observed a high prevalence of <i>BRCA1</i> epimutation in blood cells from early-onset TNBC patients with no cancer-predisposing PVs (38/112, 33.9% [95% confidence interval: 25.4–43.6%]) as compared to early-onset patients with cancer-predisposing PVs (1/87, 1.1% [0.1–7.1%], <i>p</i> value &lt; 0.001) and late-onset patients (11/93, 11.8% [6.3–20.6%], <i>p</i> value &lt; 0.001). These differences remained significant when restricting to epimutations with low variant epiallele frequencies (VEF under 1%). Our results highlight the role of constitutional <i>BRCA1</i> epimutations in early-onset TNBC risk and call for their integration into multifactorial models used to compute personalized breast cancer risk. </p>

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High prevalence of constitutional BRCA1 epimutation in patients with early-onset triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月3日

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  • Mathias Schwartz,
  • Sabrina Ibadioune,
  • Hélène Delhomelle,
  • Solenn Barraud,
  • Sandrine M. Caputo,
  • Olfa Trabelsi-Grati,
  • Marie-Charlotte Villy,
  • Anthony Laugé,
  • Roseline Tang,
  • Etienne Rouleau,
  • Emmanuelle Mouret-Fourme,
  • Dominique Stoppa-Lyonnet,
  • Éric Pasmant,
  • Lisa Golmard,
  • Chrystelle Colas,
  • Ivan Bièche

摘要

Between 5 and 8% of the general population carry a constitutional methylation of the BRCA1 promoter (“epimutation”). Several studies have suggested that these BRCA1 epimutations confer an increased risk of breast cancer, in particular triple-negative breast cancer (TNBC), with an earlier onset than in the general population. However, those studies relied on very few patients with early-onset TNBC. Using specific Methylation-Sensitive High-Resolution Melting, we assessed BRCA1 epimutation prevalence in a large cohort of 112 early-onset (≤ 30 years-old) TNBC patients with no genetic cancer-predisposing pathogenic variants (PVs). We compared this cohort to 87 early-onset TNBC patients carrying cancer-predisposing PVs and to 93 late-onset (≥ 70 years-old) TNBC with no cancer-predisposing PVs. We observed a high prevalence of BRCA1 epimutation in blood cells from early-onset TNBC patients with no cancer-predisposing PVs (38/112, 33.9% [95% confidence interval: 25.4–43.6%]) as compared to early-onset patients with cancer-predisposing PVs (1/87, 1.1% [0.1–7.1%], p value < 0.001) and late-onset patients (11/93, 11.8% [6.3–20.6%], p value < 0.001). These differences remained significant when restricting to epimutations with low variant epiallele frequencies (VEF under 1%). Our results highlight the role of constitutional BRCA1 epimutations in early-onset TNBC risk and call for their integration into multifactorial models used to compute personalized breast cancer risk.