Analysis of rare disruptive germline mutations in 2,135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes

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

doi:10.1016/j.annonc.2022.09.152

Analysis of rare disruptive germline mutations in 2,135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes

C Loveday
, A Garrett
, P Law
, S Hanks
, E Poyastro-Pearson
, J W Adlard
, J Barwell
, J Berg
, A F Brady
, C Brewer
, C Chapman
, J Cook
, R Davidson
, A Donaldson
, F Douglas
, L Greenhalgh
, A Henderson
, L Izatt
, A Kumar
, F Lalloo

Z Miedzybrodzka, P J Morrison, J Paterson, M Porteous, M T Rogers, L Walker, D Eccles, D G Evans, K Snape, H Hanson, R S Houlston, C Turnbull^* (Corresponding Author), Breast and Ovarian Cancer Susceptibility Collaboration

^*Corresponding author for this work

St James's University Hospital
Leicestershire Genetics Centre, University Hospitals of Leicester National Health Service (NHS) Trust
University of Dundee
North West Thames Regional Genetics Service
Royal Devon and Exeter Hospital
Birmingham Women's Hospital
Sheffield Regional Genetics Service, Sheffield Children’s NHS Foundation Trust
West of Scotland Regional Genetics Service
University Hospitals Bristol and Weston NHS Foundation Trust
Newcastle upon Tyne Hospitals NHS Foundation Trust
Cheshire and Merseyside Clinical Genetics Service, Alder Hey Children’s NHS Foundation Trust
South East Thames Regional Genetics Service, Guy′s and St. Thomas NHS Foundation Trust
Great Ormond Street Hospital for Children NHS Trust
Queen's University Belfast
Cambridge University Hospitals NHS Foundation Trust
University Hospital of Wales
Oxford Radcliffe Hospitals NHS Trust
University of Southampton
Institute of Cancer Research
Royal Marsden NHS Foundation Trust
Manchester University NHS Foundation Trust
Western General Hospital, Edinburgh

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

14 Downloads (Pure)

Abstract

BACKGROUND: Breast cancer has a significant heritable basis, of which approximately 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 2,135 invasive breast cancer cases recruited via the BOCS 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), iv) concomitant ovarian cancer. We undertook exome sequencing of cases and performed 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 = 10.6) down to a population minor allele frequency of 4.6 x 10 -5 (1 in 10,799, less than one tenth that of BRCA1)and of PALB2-like risk (odds ratio = 5.0) down to a population minor allele frequency of 2.8 x 10 -4 (1 in 1,779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (odds ratio = 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.

Original language	English
Pages (from-to)	1318-1327
Number of pages	9
Journal	Annals of Oncology
Volume	33
Issue number	12
Early online date	17 Sept 2022
DOIs	https://doi.org/10.1016/j.annonc.2022.09.152
Publication status	Published - Dec 2022

Bibliographical note

Acknowledgements
We thank all the subjects and families that participated in the research. We thank those at the ICR, past and present, for their assistance in patient recruitment, sample management, and management of the sequencing facility. We are grateful to all the clinicians and counsellors in The Breast and Ovarian Cancer Susceptibility Collaboration who have contributed to the recruitment and collection of samples. The full list of contributors is provided in the Appendix.

Funding
This work was supported by Cancer Research UK [grants numbers C8620/A8372, C8620/A8857]; the Institute of Cancer Research (no grant number); NHS to the Institute of Cancer Research and Royal Marsden ras part of a joint entity referred to as the National Institute of Health Research Specialist Biomedical Research Centre for Cancer.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

breast cancer
genetic susceptibility
CANCER SUSCEPTIBILITY GENE
whole-exome sequencing
rare-variant burden testing

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Loveday_etal_ESMO_Analysis_of_Rare_VOR
0923-7534/© 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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Cite this

Loveday, C., Garrett, A., Law, P., Hanks, S., Poyastro-Pearson, E., Adlard, J. W., Barwell, J., Berg, J., Brady, A. F., Brewer, C., Chapman, C., Cook, J., Davidson, R., Donaldson, A., Douglas, F., Greenhalgh, L., Henderson, A., Izatt, L., Kumar, A., ... Breast and Ovarian Cancer Susceptibility Collaboration (2022). Analysis of rare disruptive germline mutations in 2,135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes. Annals of Oncology, 33(12), 1318-1327. https://doi.org/10.1016/j.annonc.2022.09.152

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, Eccles, D, Evans, DG, Snape, K, Hanson, H, Houlston, RS, Turnbull, C & Breast and Ovarian Cancer Susceptibility Collaboration 2022, 'Analysis of rare disruptive germline mutations in 2,135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes', Annals of Oncology, vol. 33, no. 12, pp. 1318-1327. https://doi.org/10.1016/j.annonc.2022.09.152

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title = "Analysis of rare disruptive germline mutations in 2,135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes",

abstract = "BACKGROUND: Breast cancer has a significant heritable basis, of which approximately 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 2,135 invasive breast cancer cases recruited via the BOCS 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), iv) concomitant ovarian cancer. We undertook exome sequencing of cases and performed 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 = 10.6) down to a population minor allele frequency of 4.6 x 10 -5 (1 in 10,799, less than one tenth that of BRCA1)and of PALB2-like risk (odds ratio = 5.0) down to a population minor allele frequency of 2.8 x 10 -4 (1 in 1,779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (odds ratio = 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.",

keywords = "breast cancer, genetic susceptibility, CANCER SUSCEPTIBILITY GENE, whole-exome sequencing, rare-variant burden testing",

author = "C Loveday and A Garrett and P Law and S Hanks and E Poyastro-Pearson and Adlard, \{J W\} and J Barwell and J Berg and Brady, \{A F\} and C Brewer and C Chapman and J Cook and R Davidson and A Donaldson and F Douglas and L Greenhalgh and A Henderson and L Izatt and A Kumar and F Lalloo and Z Miedzybrodzka and Morrison, \{P J\} and J Paterson and M Porteous and Rogers, \{M T\} and L Walker and D Eccles and Evans, \{D G\} and K Snape and H Hanson and Houlston, \{R S\} and C Turnbull and \{Breast and Ovarian Cancer Susceptibility Collaboration\}",

note = "Acknowledgements We thank all the subjects and families that participated in the research. We thank those at the ICR, past and present, for their assistance in patient recruitment, sample management, and management of the sequencing facility. We are grateful to all the clinicians and counsellors in The Breast and Ovarian Cancer Susceptibility Collaboration who have contributed to the recruitment and collection of samples. The full list of contributors is provided in the Appendix. Funding This work was supported by Cancer Research UK [grants numbers C8620/A8372, C8620/A8857]; the Institute of Cancer Research (no grant number); NHS to the Institute of Cancer Research and Royal Marsden ras part of a joint entity referred to as the National Institute of Health Research Specialist Biomedical Research Centre for Cancer.",

year = "2022",

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doi = "10.1016/j.annonc.2022.09.152",

language = "English",

volume = "33",

pages = "1318--1327",

journal = "Annals of Oncology",

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publisher = "Elsevier Limited",

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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 - Eccles, D

AU - Evans, D G

AU - Snape, K

AU - Hanson, H

AU - Houlston, R S

AU - Turnbull, C

AU - Breast and Ovarian Cancer Susceptibility Collaboration

N1 - Acknowledgements We thank all the subjects and families that participated in the research. We thank those at the ICR, past and present, for their assistance in patient recruitment, sample management, and management of the sequencing facility. We are grateful to all the clinicians and counsellors in The Breast and Ovarian Cancer Susceptibility Collaboration who have contributed to the recruitment and collection of samples. The full list of contributors is provided in the Appendix. Funding This work was supported by Cancer Research UK [grants numbers C8620/A8372, C8620/A8857]; the Institute of Cancer Research (no grant number); NHS to the Institute of Cancer Research and Royal Marsden ras part of a joint entity referred to as the National Institute of Health Research Specialist Biomedical Research Centre for Cancer.

PY - 2022/12

Y1 - 2022/12

N2 - BACKGROUND: Breast cancer has a significant heritable basis, of which approximately 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 2,135 invasive breast cancer cases recruited via the BOCS 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), iv) concomitant ovarian cancer. We undertook exome sequencing of cases and performed 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 = 10.6) down to a population minor allele frequency of 4.6 x 10 -5 (1 in 10,799, less than one tenth that of BRCA1)and of PALB2-like risk (odds ratio = 5.0) down to a population minor allele frequency of 2.8 x 10 -4 (1 in 1,779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (odds ratio = 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 approximately 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 2,135 invasive breast cancer cases recruited via the BOCS 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), iv) concomitant ovarian cancer. We undertook exome sequencing of cases and performed 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 = 10.6) down to a population minor allele frequency of 4.6 x 10 -5 (1 in 10,799, less than one tenth that of BRCA1)and of PALB2-like risk (odds ratio = 5.0) down to a population minor allele frequency of 2.8 x 10 -4 (1 in 1,779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (odds ratio = 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 GENE

KW - whole-exome sequencing

KW - rare-variant burden testing

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 -

Analysis of rare disruptive germline mutations in 2,135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes

Abstract

Bibliographical note

UN SDGs

Keywords

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