Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk.
Cancer Epidemiol Biomarkers Prev
; 28(7): 1117-1126, 2019 07.
Article
en En
| MEDLINE
| ID: mdl-30948450
ABSTRACT
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 (â¼100 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 = 2.57; P = 0.001) and a deletion at CYP2A7 (OR = 1.90; P = 0.007) that were strongly associated with HGSOC risk (OR = 3.02; P = 8.98 × 10-5). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P = 2.94 × 10-47). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR = 0.33; P = 9.5 × 10-2), and somatic deletions correlated with ERBB4 downregulation (P = 7.05 × 10-5). 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 = 2.7 × 10-7), and another at 8p21.2 (OR = 0.52; P = 0.002) that was present somatically where it correlated with lower GNRH1 expression (P = 5.9 × 10-5).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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Estudio de Asociación del Genoma Completo
/
Variaciones en el Número de Copia de ADN
/
Carcinoma Epitelial de Ovario
Tipo de estudio:
Etiology_studies
/
Observational_studies
/
Risk_factors_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
Cancer Epidemiol Biomarkers Prev
Asunto de la revista:
BIOQUIMICA
/
EPIDEMIOLOGIA
/
NEOPLASIAS
Año:
2019
Tipo del documento:
Article