Journal article
Integration of tumour sequencing and case–control data to assess pathogenicity of RAD51C missense variants in familial breast cancer
BWX Lim, N Li, SM Rowley, ER Thompson, S McInerny, M Zethoven, RJ Scott, L Devereux, EK Sloan, PA James, IG Campbell
Npj Breast Cancer | NATURE PORTFOLIO | Published : 2022
Abstract
While protein-truncating variants in RAD51C have been shown to predispose to triple-negative (TN) breast cancer (BC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. The frequency of rare RAD51C MS variants was assessed in the BEACCON study of 5734 familial BC cases and 14,382 population controls, and findings were integrated with tumour sequencing data from 21 cases carrying a candidate variant. Collectively, a significant enrichment of rare MS variants was detected in cases (MAF 0.5 (OR 3.95, 95% CI 1.40–12.01, p = 0.006). Sequencing of 21 tumours from 20 heterozygous and 1 homozygous carriers of nine candidate MS variants identified four cases with bi..
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Grants
Awarded by Cancer Council Victoria
Funding Acknowledgements
The authors thank all the participants of the ViP and Lifepool studies for donating their DNA samples and clinical information. We also thank Norah Grewal, the ViP study site principal investigators Geoffrey Lindeman, Marion Harris, Tom John, Ingrid Winship and Yoland Antill, and the staff at the Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Monash Health, Cabrini Health and Barwon Health Familial Cancer Centres and the Austin and Tasmanian Clinical Genetics Services, who enroled participants and provided clinical data. We thank the following staff from Peter MacCallum Cancer Centre: Tim Semple and Gisela Mir Arnau from Molecular Genomics core facility, and Steven Macaskill from Pathology for sequencing the tumour DNA, Kaushalya Amarasinghe, Niko Thio and Richard Lupat from Bioinformatics core facility for helping with the bioinformatic analysis, Metta Jana from Centre for Advanced Histology and Microscopy for preparing sections of tumour blocks, and Heather Thorne, Lynda Williams and Genna Glavich from kConFab for assisting with obtaining the tumour blocks. This work was supported by the National Breast Cancer Foundation (IF-15-004, I.G.C. and P.A.J.), Cancer Australia/National Breast Cancer Foundation (PdCCRS_1107870, I.G.C. and P.A.J.), the Victorian Cancer Agency (Tumor Stream Grant, P.A.J.) and the National Health and Medical Research Council of Australia (GNT1023698, P.A.J.; GNT1041975, I.G.C.). E.K.S. is supported by NHMRC GNT1147498 and NBCF IIRS-20025. N.L. and E.K.S. are supported by Cancer Council Victoria.