University of Oulu

Kumpula TA, Vorimo S, Mattila TT, O’Gorman L, Astuti G, Tervasmäki A, et al. (2023) Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility. PLoS Genet 19(8): e1010889.

Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility

Saved in:
Author: Kumpula, Timo A.1; Vorimo, Sandra1; Mattila, Taneli T.2;
Organizations: 1Laboratory of Cancer Genetics and Tumor Biology, Research Unit of Translational Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland
2Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland
3Department of Human Genetics and Radboud Institute of Medical Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
4Department of Surgery, Oulu University Hospital and University of Oulu, Oulu, Finland
5Department of Clinical Genetics, Medical Research Center Oulu and PEDEGO Research Unit, Oulu University Hospital and University of Oulu, Oulu, Finland
6Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
7Northern Finland Laboratory Centre Nordlab, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.8 MB)
Persistent link:
Language: English
Published: Public Library of Science, 2023
Publish Date: 2023-10-23


Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10–7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31–8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62–31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

see all

Series: PLoS genetics
ISSN: 1553-7390
ISSN-E: 1553-7404
ISSN-L: 1553-7390
Volume: 19
Issue: 8
Article number: e1010889
DOI: 10.1371/journal.pgen.1010889
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work was supported by the Academy of Finland [307808, KP], the Cancer Foundation of Finland sr (KP) and Sigrid Jusélius foundation (RW, KP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Academy of Finland Grant Number: 307808
Detailed Information: 307808 (Academy of Finland Funding decision)
Copyright information: © 2023 Kumpula et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.