TY - JOUR
T1 - Analysis of rare disruptive germline mutations in 2,135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes
AU - Loveday, C.
AU - Garrett, A.
AU - Law, P.
AU - Hanks, S.
AU - Poyastro-Pearson, E.
AU - Adlard, J. W.
AU - Barwell, J.
AU - Berg, J.
AU - Brady, A. F.
AU - Brewer, C.
AU - Chapman, C.
AU - Cook, J.
AU - Davidson, R.
AU - Donaldson, A.
AU - Douglas, F.
AU - Greenhalgh, L.
AU - Henderson, A.
AU - Izatt, L.
AU - Kumar, A.
AU - Lalloo, F.
AU - Miedzybrodzka, Z.
AU - Morrison, P. J.
AU - Paterson, J.
AU - Porteous, M.
AU - Rogers, M. T.
AU - Walker, L.
AU - Breast and Ovarian Cancer Susceptibility Collaboration
AU - Eccles, D.
AU - Evans, D. G.
AU - Snape, K.
AU - Hanson, H.
AU - Houlston, R. S.
AU - Turnbull, C.
N1 - Funding Information:
This work was supported by Cancer Research UK [grants numbers C8620/A8372, C8620/A8857]; the Institute of Cancer Research [no applicable grant number]; and the National Health Service funding to the Royal Marsden / Institute of Cancer Research National Institute of Health Research Specialist Biomedical Research Centre for Cancer [no applicable grant numbers].
Copyright:
© 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
PY - 2022/12
Y1 - 2022/12
N2 - Background: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility.Patients and methods: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. Eligibility criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD.Results: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10 −5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10 −4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM.Conclusions: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.
AB - Background: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility.Patients and methods: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. Eligibility criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD.Results: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10 −5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10 −4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM.Conclusions: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.
KW - Breast cancer
KW - Genetic susceptibility
KW - Cancer susceptibility genes
KW - Whole exome sequencing
KW - Rare variant burden testing
KW - cancer susceptibility genes
KW - breast cancer
KW - genetic susceptibility
KW - rare-variant burden testing
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85141320959&partnerID=8YFLogxK
U2 - 10.1016/j.annonc.2022.09.152
DO - 10.1016/j.annonc.2022.09.152
M3 - Article
C2 - 36122798
SN - 0923-7534
VL - 33
SP - 1318
EP - 1327
JO - Annals of Oncology
JF - Annals of Oncology
IS - 12
ER -