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<p>Pathogenic coding variants in <i>BRCA1</i>, <i>BRCA2</i> and <i>PALB2</i> confer hereditary breast/ovarian cancer risk, yet these regions comprise less than 10% of the genomic footprint of these genes, leaving most sequence unexplored. We investigated the contribution of non-coding variation to hereditary breast cancer by analyzing intronic variants and 5′ upstream regions of <i>BRCA1</i>, <i>BRCA2</i> and <i>PALB2</i> in the BEACCON case–control study of over 11,000 participants. Full-gene sequencing showed that 46.3% of cases carried at least one rare non-coding variant. This was associated with a modest increase in breast cancer risk (OR = 1.2, <i>p</i> &lt; 0.0001), most likely reflecting the presence of a small proportion of pathogenic variants within a larger background of predominantly neutral variation. Stronger enrichment was observed for triple-negative disease, particularly for <i>BRCA1</i> (OR = 1.5, <i>p</i> = 0.0001). Tumor sequencing of 42 high-priority variants identified 11 (26.2%) with wild-type allele loss and high homologous recombination deficiency. Functional CRISPR/Cas9 knock-in assays in MCF10A cells confirmed that two deep intronic variants created aberrant splice sites, disrupted splicing and impacted transcript expression.</p>

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Investigating the contribution of rare non-coding variants in BRCA1, BRCA2 and PALB2 to hereditary breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月4日

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  • Qihong Zhao,
  • Na Li,
  • Evanny Marinovic,
  • Simone McInerny,
  • Maia Zethoven,
  • Lisa Devereux,
  • Daffodil M. Canson,
  • Amanda B. Spurdle,
  • Rodney J. Scott,
  • Paul A. James,
  • Ian G. Campbell

摘要

Pathogenic coding variants in BRCA1, BRCA2 and PALB2 confer hereditary breast/ovarian cancer risk, yet these regions comprise less than 10% of the genomic footprint of these genes, leaving most sequence unexplored. We investigated the contribution of non-coding variation to hereditary breast cancer by analyzing intronic variants and 5′ upstream regions of BRCA1, BRCA2 and PALB2 in the BEACCON case–control study of over 11,000 participants. Full-gene sequencing showed that 46.3% of cases carried at least one rare non-coding variant. This was associated with a modest increase in breast cancer risk (OR = 1.2, p < 0.0001), most likely reflecting the presence of a small proportion of pathogenic variants within a larger background of predominantly neutral variation. Stronger enrichment was observed for triple-negative disease, particularly for BRCA1 (OR = 1.5, p = 0.0001). Tumor sequencing of 42 high-priority variants identified 11 (26.2%) with wild-type allele loss and high homologous recombination deficiency. Functional CRISPR/Cas9 knock-in assays in MCF10A cells confirmed that two deep intronic variants created aberrant splice sites, disrupted splicing and impacted transcript expression.