Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
Hakkaart, C. ; Ehrencrona, H. LU
and Walker, Logan C.
(2022)
In Communications Biology
5(1).
- Abstract
- 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... (More)
- 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. © 2022. The Author(s). (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/0964c6a6-cdc1-43e9-b451-a6a5cecc9680
- author
- Hakkaart, C.
; Ehrencrona, H.
LU
and Walker, Logan C.
- author collaboration
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- BRCA1 protein, BRCA1 protein, human, BRCA2 protein, BRCA2 protein, human, messenger RNA, breast tumor, copy number variation, female, genetic predisposition, genetics, heterozygote, human, pathology, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Heterozygote, Humans, RNA, Messenger
- in
- Communications Biology
- volume
- 5
- issue
- 1
- article number
- 1061
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85139349547
- pmid:36203093
- ISSN
- 2399-3642
- DOI
- 10.1038/s42003-022-03978-6
- language
- English
- LU publication?
- yes
- id
- 0964c6a6-cdc1-43e9-b451-a6a5cecc9680
- date added to LUP
- 2022-12-20 10:34:35
- date last changed
- 2022-12-22 03:00:20
@article{0964c6a6-cdc1-43e9-b451-a6a5cecc9680,
abstract = {{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. © 2022. The Author(s).}},
author = {{Hakkaart, C. and Ehrencrona, H. and Walker, Logan C.}},
issn = {{2399-3642}},
keywords = {{BRCA1 protein; BRCA1 protein, human; BRCA2 protein; BRCA2 protein, human; messenger RNA; breast tumor; copy number variation; female; genetic predisposition; genetics; heterozygote; human; pathology; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; DNA Copy Number Variations; Female; Genetic Predisposition to Disease; Heterozygote; Humans; RNA, Messenger}},
language = {{eng}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Communications Biology}},
title = {{Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers}},
url = {{http://dx.doi.org/10.1038/s42003-022-03978-6}},
doi = {{10.1038/s42003-022-03978-6}},
volume = {{5}},
year = {{2022}},
}