Whole-exome sequencing of BRCA-negative breast cancer patients and case–control analyses identify variants associated with breast cancer susceptibility

Human Genomics

Research

Pei-Yi Ong¹  Soo-Chin Lee²  Chia Wei Lim³  Matthew Wong⁴  Matthew Khine Myint⁴  Ning Yuan Lee⁴  Aseervatham Anusha Amali⁴  Melissa Hum⁴  Wei Kiat Lim⁴  Ann S. G. Lee⁵  Min-Han Tan⁶  Ru Jin Tay⁶  Jens Samol⁷  Peter Ang⁸ 

[1] Department of Hematology-Oncology, National University Cancer Institute, Singapore (NCIS), National University Health System, 5 Lower Kent Ridge Road, 119074, Singapore, Singapore;Department of Hematology-Oncology, National University Cancer Institute, Singapore (NCIS), National University Health System, 5 Lower Kent Ridge Road, 119074, Singapore, Singapore;Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, 117597, Singapore, Singapore;Cancer Science Institute, Singapore (CSI), National University of Singapore, 14 Medical Dr, 117599, Singapore, Singapore;Department of Personalised Medicine, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore;Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Crescent, 169610, Singapore, Singapore;Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Crescent, 169610, Singapore, Singapore;Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, 117593, Singapore, Singapore;SingHealth Duke-NUS Oncology Academic Clinical Programme (ONCO ACP), Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore, Singapore;Lucence Diagnostics Pte Ltd, 211 Henderson Road, 159552, Singapore, Singapore;Medical Oncology Department, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore;Johns Hopkins University, 21218, Baltimore, MD, USA;Oncocare Cancer Centre, Gleneagles Medical Centre, 6 Napier Road, 258499, Singapore, Singapore;

关键词: Breast cancer;    BRCA;    Whole-exome sequencing;    Germline variants;    Case–control analysis;   

DOI  :  10.1186/s40246-022-00435-7

 received in 2022-08-15, accepted in 2022-11-14,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundFor the majority of individuals with early-onset or familial breast cancer referred for genetic testing, the genetic basis of their familial breast cancer remains unexplained. To identify novel germline variants associated with breast cancer predisposition, whole-exome sequencing (WES) was performed.MethodsWES on 290 BRCA1/BRCA2-negative Singaporeans with early-onset breast cancer and/or a family history of breast cancer was done. Case–control analysis against the East-Asian subpopulation (EAS) from the Genome Aggregation Database (gnomAD) identified variants enriched in cases, which were further selected by occurrence in cancer gene databases. Variants were further evaluated in repeated case–control analyses using a second case cohort from the database of Genotypes and Phenotypes (dbGaP) comprising 466 early-onset breast cancer patients from the United States, and a Singapore SG10K_Health control cohort.ResultsForty-nine breast cancer-associated germline pathogenic variants in 37 genes were identified in Singapore cases versus gnomAD (EAS). Compared against SG10K_Health controls, 13 of 49 variants remain significantly enriched (False Discovery Rate (FDR)-adjusted p < 0.05). Comparing these 49 variants in dbGaP cases against gnomAD (EAS) and SG10K_Health controls revealed 23 concordant variants that were significantly enriched (FDR-adjusted p < 0.05). Fourteen variants were consistently enriched in breast cancer cases across all comparisons (FDR-adjusted p < 0.05). Seven variants in GPRIN2, NRG1, MYO5A, CLIP1, CUX1, GNAS and MGA were confirmed by Sanger sequencing.ConclusionsIn conclusion, we have identified pathogenic variants in genes associated with breast cancer predisposition. Importantly, many of these variants were significant in a second case cohort from dbGaP, suggesting that the strategy of using case–control analysis to select variants could potentially be utilized for identifying variants associated with cancer susceptibility.

【 授权许可】

CC BY   
© The Author(s) 2022. corrected publication 2022

【 图 表 】

12888_2022_4365_Article_IEq4.gif

12888_2022_4365_Article_IEq1.gif

Fig. 1

12982_2022_119_Article_IEq87.gif

Fig. 3

12888_2022_4482_Article_IEq1.gif