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

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  • Christopher Hakkaart
  • John F. Pearson
  • Louise Marquart
  • Joe Dennis
  • George A. R. Wiggins
  • Daniel R. Barnes
  • Bridget A. Robinson
  • Peter D. Mace
  • Kristiina Aittomäki
  • Irene L. Andrulis
  • Banu K. Arun
  • Jacopo Azzollini
  • Judith Balmaña
  • Rosa B. Barkardottir
  • Sami Belhadj
  • Lieke Berger
  • Marinus J. Blok
  • Susanne E. Boonen
  • Julika Borde
  • Angela R. Bradbury
  • Joan Brunet
  • Saundra S Buys
  • Maria A. Caligo
  • Ian Campbell
  • Wendy K. Chung
  • Kathleen B. M. Claes
  • Marie-Agnès Collonge-Rame
  • Jackie Cook
  • Casey Cosgrove
  • Fergus J. Couch
  • Mary B. Daly
  • Sita Dandiker
  • Rosemarie Davidson
  • Miguel de la Hoya
  • Robin de Putter
  • Capucine Delnatte
  • Mallika Dhawan
  • Orland Diez
  • Yuan Chun Ding
  • Susan M. Domchek
  • Alan Donaldson
  • Jacqueline Eason
  • Douglas F. Easton
  • Hans Ehrencrona
  • Christoph Engel
  • D. Gareth Evans
  • Ulrike Faust
  • Lidia Feliubadaló
  • Florentia Fostira
  • Hansen, Thomas van Overeem
  • Rossing, Caroline Maria
  • GEMO Study Collaborators
  • EMBRACE Collaborators
  • SWE-BRCA Investigators
  • kConFab Investigators
  • HEBON Investigators

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 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 BRCA1 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 SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 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 BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Original languageEnglish
Article number1061
JournalCommunications Biology
Number of pages15
Publication statusPublished - 2022

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© 2022. The Author(s).

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