TY - JOUR
T1 - Genome-wide analysis of common copy number variation and epithelial ovarian cancer risk
AU - Reid, Brett M.
AU - Permuth, Jennifer B.
AU - Ann Chen, Y.
AU - Fridley, Brooke L.
AU - Iversen, Edwin S.
AU - Chen, Zhihua
AU - Jim, Heather
AU - Vierkant, Robert A.
AU - Cunningham, Julie M.
AU - Barnholtz-Sloan, Jill S.
AU - Narod, Steven
AU - Risch, Harvey
AU - Schildkraut, Joellen M.
AU - Goode, Ellen L.
AU - Monteiro, Alvaro N.
AU - Sellers, Thomas A.
N1 - Publisher Copyright:
2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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 3,500 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 (100 kb) regions within the 610k set and one small (<5 kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR ¼ 2.57; P ¼ 0.001) and a deletion at CYP2A7 (OR ¼ 1.90; P ¼ 0.007) that were strongly associated with HGSOC risk (OR ¼ 3.02; P ¼ 8.98 105). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P ¼ 2.94 1047). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR ¼ 0.33; P ¼ 9.5 102), and somatic deletions correlated with ERBB4 downregulation (P ¼ 7.05 105). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR ¼ 0.28; P ¼ 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P ¼ 2.7 107), and another at 8p21.2 (OR ¼ 0.52; P ¼ 0.002) that was present somatically where it correlated with lower GNRH1 expression (P ¼ 5.9 105). 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.
AB - 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 3,500 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 (100 kb) regions within the 610k set and one small (<5 kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR ¼ 2.57; P ¼ 0.001) and a deletion at CYP2A7 (OR ¼ 1.90; P ¼ 0.007) that were strongly associated with HGSOC risk (OR ¼ 3.02; P ¼ 8.98 105). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P ¼ 2.94 1047). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR ¼ 0.33; P ¼ 9.5 102), and somatic deletions correlated with ERBB4 downregulation (P ¼ 7.05 105). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR ¼ 0.28; P ¼ 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P ¼ 2.7 107), and another at 8p21.2 (OR ¼ 0.52; P ¼ 0.002) that was present somatically where it correlated with lower GNRH1 expression (P ¼ 5.9 105). 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.
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U2 - 10.1158/1055-9965.EPI-18-0833
DO - 10.1158/1055-9965.EPI-18-0833
M3 - Article
C2 - 30948450
AN - SCOPUS:85068805761
SN - 1055-9965
VL - 28
SP - 1117
EP - 1126
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 7
ER -