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 LallooZ 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

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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 languageEnglish
Pages (from-to)1318-1327
Number of pages9
JournalAnnals of Oncology
Volume33
Issue number12
Early online date17 Sept 2022
DOIs
Publication statusPublished - 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.

Keywords

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

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