Copy Number Variation Analysis in Familial BRCA1/2-Negative Finnish Breast and Ovarian Cancer

Minna Kankuri-Tammilehto,Kirsi M Kuusisto,Oyediran Akinrinade,Satu-Leena Laasanen,Johanna Schleutker,Mauno Vihinen

doi:10.1371/journal.pone.0071802

Abstract

BackgroundInherited factors predisposing individuals to breast and ovarian cancer are largely unidentified in a majority of families with hereditary breast and ovarian cancer (HBOC). We aimed to identify germline copy number variations (CNVs) contributing to HBOC susceptibility in the Finnish population.MethodsA cohort of 84 HBOC individuals (negative for BRCA1/2-founder mutations and pre-screened for the most common breast cancer genes) and 36 healthy controls were analysed with a genome-wide SNP array. CNV-affecting genes were further studied by Gene Ontology term enrichment, pathway analyses, and database searches to reveal genes with potential for breast and ovarian cancer predisposition. CNVs that were considered to be important were validated and genotyped in 20 additional HBOC individuals (6 CNVs) and in additional healthy controls (5 CNVs) by qPCR.ResultsAn intronic deletion in the EPHA3 receptor tyrosine kinase was enriched in HBOC individuals (12 of 101, 11.9%) compared with controls (27 of 432, 6.3%) (OR = 1.96; P = 0.055). EPHA3 was identified in several enriched molecular functions including receptor activity. Both a novel intronic deletion in the CSMD1 tumor suppressor gene and a homozygous intergenic deletion at 5q15 were identified in 1 of 101 (1.0%) HBOC individuals but were very rare (1 of 436, 0.2% and 1 of 899, 0.1%, respectively) in healthy controls suggesting that these variants confer disease susceptibility.ConclusionThis study reveals new information regarding the germline CNVs that likely contribute to HBOC susceptibility in Finland. This information may be used to facilitate the genetic counselling of HBOC individuals but the preliminary results warrant additional studies of a larger study group.

Highlights

Breast cancer (BC) is the most common cancer among women in western countries, including Finland
The most important observations are that the average number of copy number variations (CNVs) was slightly higher in hereditary breast and ovarian cancer (HBOC) individuals compared with controls, and deletions were more frequent in HBOC individuals
We focused on CNVs with the following characteristics: they were enriched in HBOC individuals compared with controls and 1) affected known or potential genes contributing to HBOC predisposition (3 CNVs); or 2) they were homozygous, and carriers presented with interesting clinical outcomes (1 CNV); or 3) they were not reported in the Database of Genomic Variants and affected genes related to BC (2 CNVs)

Summary

Introduction

Breast cancer (BC) is the most common cancer among women in western countries, including Finland. Inherited BC risk is known to be associated with rare, highly penetrant variants, mainly single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels) in BRCA1 and BRCA2, which account for nearly 20% of hereditary breast and/or ovarian cancer (HBOC) cases in Finland [1,2,3]. Variants in other BRCA1/2 interacting genes, including CHEK2, PALB2, RAD51C, and Abraxas, are known to account for a low proportion of HBOC susceptibility in the Finnish population [4,5,6,7]. In addition to SNPs and small indels, copy number variations (CNVs) contribute to susceptibility to complex diseases and disorders [8]. We aimed to identify germline copy number variations (CNVs) contributing to HBOC susceptibility in the Finnish population

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