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Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus
- Source :
- Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP, Cancer Research, 79, 3, pp. 467-481, Cancer Research, 79, 467-481
- Publication Year :
- 2019
-
Abstract
- Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. Significance: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439
- Subjects :
- 0301 basic medicine
Cancer Research
Linkage disequilibrium
Cell Cycle Proteins
Genome-wide association study
Single-nucleotide polymorphism
Locus (genetics)
Carcinoma, Ovarian Epithelial
Biology
Polymorphism, Single Nucleotide
Linkage Disequilibrium
03 medical and health sciences
All institutes and research themes of the Radboud University Medical Center
0302 clinical medicine
Cell Line, Tumor
medicine
Humans
Genetic Predisposition to Disease
Scaffold/matrix attachment region
Gene
Genotyping
Ovarian Neoplasms
Genetics
Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17]
Base Sequence
Chromosome Mapping
DNA, Neoplasm
medicine.disease
Women's cancers Radboud Institute for Health Sciences [Radboudumc 17]
Cystadenocarcinoma, Serous
3. Good health
DNA-Binding Proteins
HEK293 Cells
030104 developmental biology
Oncology
Urological cancers Radboud Institute for Health Sciences [Radboudumc 15]
030220 oncology & carcinogenesis
Female
MAPEAMENTO GENÉTICO
Chromosomes, Human, Pair 9
Ovarian cancer
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 00085472
- Database :
- OpenAIRE
- Journal :
- Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP, Cancer Research, 79, 3, pp. 467-481, Cancer Research, 79, 467-481
- Accession number :
- edsair.doi.dedup.....dbc4b4bf970c49c1f08716fe796a1f05