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Hakkaart, Christopher; Pearson, John F.; Marquart, Louise; Dennis, Joe; Wiggins, George A. R.; Barnes, Daniel R.; Robinson, Bridget A.; Mace, Peter D.; Aittomäki, Kristiina; Andrulis, Irene L.; Arun, Banu K.; Azzollini, Jacopo; Balmaña, Judith; Barkardottir, Rosa B.; Belhadj, Sami; Berger, Lieke; Blok, Marinus J.; Boonen, Susanne E.; Borde, Julika; Bradbury, Angela R.; Brunet, Joan; Buys, Saundra S.; Caligo, Maria A.; Campbell, Ian; [...]

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

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  • Media type: E-Article
  • Title: Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
  • Contributor: Hakkaart, Christopher; Pearson, John F.; Marquart, Louise; Dennis, Joe; Wiggins, George A. R.; Barnes, Daniel R.; Robinson, Bridget A.; Mace, Peter D.; Aittomäki, Kristiina; Andrulis, Irene L.; Arun, Banu K.; Azzollini, Jacopo; Balmaña, Judith; Barkardottir, Rosa B.; Belhadj, Sami; Berger, Lieke; Blok, Marinus J.; Boonen, Susanne E.; Borde, Julika; Bradbury, Angela R.; Brunet, Joan; Buys, Saundra S.; Caligo, Maria A.; Campbell, Ian; [...]
  • imprint: Springer Science and Business Media LLC, 2022
  • Published in: Communications Biology
  • Language: English
  • DOI: 10.1038/s42003-022-03978-6
  • ISSN: 2399-3642
  • Keywords: General Agricultural and Biological Sciences ; General Biochemistry, Genetics and Molecular Biology ; Medicine (miscellaneous)
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic <jats:italic>BRCA1</jats:italic> or <jats:italic>BRCA2</jats:italic> variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 <jats:italic>BRCA1</jats:italic> and 10,740 <jats:italic>BRCA2</jats:italic> pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in <jats:italic>BRCA1</jats:italic> suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping <jats:italic>SULT1A1</jats:italic> suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in <jats:italic>BRCA1</jats:italic> pathogenic variant carriers. Functional analyses of <jats:italic>SULT1A1</jats:italic> showed that reduced mRNA expression in pathogenic <jats:italic>BRCA1</jats:italic> variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in <jats:italic>BRCA1</jats:italic> plus <jats:italic>SULT1A1</jats:italic> deletions contribute to variable breast cancer risk in <jats:italic>BRCA1</jats:italic> carriers.</jats:p>
  • Access State: Open Access