39P - Search for rare copy number variants associated with hereditary breast cancer in Finnish case-control cohorts

Background

For breast cancer susceptibility, copy number variants (CNVs) represent a class of genetic variation that has been poorly studied and could therefore explain a part of the unknown hereditary risk. CNVs are generally defined as gains or losses of genomic segments with a size of > 1 kilobase. To evaluate the role of rare CNVs in breast cancer susceptibility, here we have performed a whole-exome sequencing based CNV analysis for Northern Finnish high-risk breast cancer cases and verified obtained results with optical genome mapping.

Methods

Optical genome mapping and exome sequencing were performed for 110 high-risk breast cancer cases. All detected rare recurrent candidate CNVs were characterized at nucleotide level with long-read sequencing and genotyped in geographically matched case-control cohorts (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls).

Results

Three recurrent alterations were detected: a 31 kb deletion co-occurring with a 3 kb retrotransposon insertion in RAD52, a partial 64 kb duplication in RAD51C and a 13 kb deletion in HSD17B14. Of these, RAD52 and RAD51C are involved in DNA damage response pathway, whereas HSD17B14 encodes a protein involved in steroid hormone metabolism in human tissues, including mammary fat. The CNVs that disrupted RAD52and HSD17B14 genes showed around three-fold enrichment (carrier frequencies 2.5% and 2.9%, respectively) among cases with a family history of the disease and/or early disease onset compared to controls (0.9%), suggesting a role for these alterations in breast cancer susceptibility. The RAD51C duplication had two-fold frequency in breast cancer cases compared to controls. Interestingly, we also identified several double-mutants suggesting the potential role of combined effect of moderate-risk alleles in inherited breast cancer risk.

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

T.A. Kumpula.

Funding

Academy of Finland, the Cancer Foundation of Finland and Sigrid Juselius Foundation.

Disclosure

All authors have declared no conflicts of interest.