Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk
Menée in silico et à partir des données du projet "The Cancer Genome Atlas" portant sur 3 500 génotypes, cette étude d'association sur le génome entier analyse l'association entre des variations du nombre de copies de variants génétiques et le risque de cancer épithélial de l'ovaire
Background : Germline DNA copy number variation (CNV) is a ubiquitous source of genetic variation and remains largely unexplored in association with epithelial ovarian cancer (EOC) risk. Methods : CNV was quantified in the DNA of approximately 3500 cases and controls genotyped with the Illumina 610k and HumanOmni2.5M arrays. We performed a genome-wide association study of common (>1%) CNV regions (CNVRs) with EOC and high-grade serous (HGSOC) risk and, using The Cancer Genome Atlas (TCGA), performed in silico analyses of tumor-gene expression. Results : Three CNVRs were associated (P<0.01) with EOC risk: two large (~100kb) regions within the 610k set and one small (<5kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR=2.57, P=0.001) and a deletion at CYP2A7 (OR=1.90, P=0.007) that was strongly associated with HGSOC risk (OR=3.02, P=8.98x10-5). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P=2.94x10-47). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR=0.33, P=9.5x10-2) and somatic deletions correlated with ERBB4 downregulation (P=7.05x10-5). Five CNVRs were associated with HGSOC including two reduced-risk deletions: one at 1p36.33 (OR=0.28, P=0.001) that correlated with lower CDKIIA expression in TCGA tumors (P=2.7x10-7), and another at 8p21.2 (OR=0.52, P=0.002) that was present somatically where it correlated with lower GNRH1 expression (P=5.9x10-5). Conclusions : Though CNV appears to not contribute largely to EOC susceptibility, a number of low-to-common frequency variants may influence the risk of EOC and tumor gene expression. Impact : Further research on CNV and EOC susceptibility is warranted, particularly with CNVs estimated from high-density arrays.