Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

Loveday, C; Garrett, A; Law, P; Hanks, S; Poyastro-Pearson, E; Adlard, JW; Barwell, J; Berg, J; Brady, AF; Brewer, C; Chapman, C; Cook, J; Davidson, R; Donaldson, A; Douglas, F; Greenhalgh, L; Henderson, A; Izatt, L; Kumar, A; Lalloo, F; Miedzybrodzka, Z; Morrison, PJ; Paterson, J; Porteous, M; Rogers, MT; Walker, L; Breast and Ovarian Cancer Susceptibility Collaboration,; Eccles, D; Evans, DG; Snape, K; Hanson, H; Houlston, RS; Turnbull, C

Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

Loveday, C Garrett, A Law, P Hanks, S Poyastro-Pearson, E Adlard, JW Barwell, J Berg, J Brady, AF Brewer, C Chapman, C Cook, J Davidson, R Donaldson, A Douglas, F Greenhalgh, L Henderson, A Izatt, L Kumar, A Lalloo, F Miedzybrodzka, Z Morrison, PJ Paterson, J Porteous, M Rogers, MT Walker, L Breast and Ovarian Cancer Susceptibility Collaboration, Eccles, D Evans, DG Snape, K Hanson, H Houlston, RS Turnbull, C

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Ann Oncol, 2022, 33, (12), pp. 1318-1327
Issue Date:: 2022-12

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Field	Value	Language
dc.contributor.author	Loveday, C
dc.contributor.author	Garrett, A
dc.contributor.author	Law, P
dc.contributor.author	Hanks, S
dc.contributor.author	Poyastro-Pearson, E
dc.contributor.author	Adlard, JW
dc.contributor.author	Barwell, J
dc.contributor.author	Berg, J
dc.contributor.author	Brady, AF
dc.contributor.author	Brewer, C
dc.contributor.author	Chapman, C
dc.contributor.author	Cook, J
dc.contributor.author	Davidson, R
dc.contributor.author	Donaldson, A
dc.contributor.author	Douglas, F
dc.contributor.author	Greenhalgh, L
dc.contributor.author	Henderson, A
dc.contributor.author	Izatt, L
dc.contributor.author	Kumar, A
dc.contributor.author	Lalloo, F
dc.contributor.author	Miedzybrodzka, Z
dc.contributor.author	Morrison, PJ
dc.contributor.author	Paterson, J
dc.contributor.author	Porteous, M
dc.contributor.author	Rogers, MT
dc.contributor.author	Walker, L
dc.contributor.author	Breast and Ovarian Cancer Susceptibility Collaboration,
dc.contributor.author	Eccles, D
dc.contributor.author	Evans, DG
dc.contributor.author	Snape, K
dc.contributor.author	Hanson, H
dc.contributor.author	Houlston, RS
dc.contributor.author	Turnbull, C
dc.date.accessioned	2023-08-23T02:44:27Z
dc.date.available	2022-09-01
dc.date.available	2023-08-23T02:44:27Z
dc.date.issued	2022-12
dc.identifier.citation	Ann Oncol, 2022, 33, (12), pp. 1318-1327
dc.identifier.issn	0923-7534
dc.identifier.issn	1569-8041
dc.identifier.uri	http://hdl.handle.net/10453/171815
dc.description.abstract	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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Ann Oncol
dc.relation.isbasedon	10.1016/j.annonc.2022.09.152
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.classification	3202 Clinical sciences
dc.subject.classification	3211 Oncology and carcinogenesis
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Adult
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Triple Negative Breast Neoplasms
dc.subject.mesh	Retrospective Studies
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Ovarian Neoplasms
dc.subject.mesh	Humans
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Ovarian Neoplasms
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Retrospective Studies
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Adult
dc.subject.mesh	Female
dc.subject.mesh	Triple Negative Breast Neoplasms
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Adult
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Triple Negative Breast Neoplasms
dc.subject.mesh	Retrospective Studies
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Ovarian Neoplasms
dc.title	Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.
dc.type	Journal Article
utslib.citation.volume	33
utslib.location.activity	England
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
utslib.copyright.status	open_access	*
dc.date.updated	2023-08-23T02:44:26Z
pubs.issue	12
pubs.publication-status	Published
pubs.volume	33
utslib.citation.issue	12

Abstract:

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.

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http://hdl.handle.net/10453/171815