| Title: |
Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus |
| Authors: |
Buckley, Melissa A.; Woods, Nicholas T.; Tyrer, Jonathan P.; Mendoza-Fandino, Gustavo; Lawrenson, Kate; Hazelett, Dennis J.; Najafabadi, Hamed S.; Gjyshi, Anxhela; Carvalho, Renato S.; Lyra, Paulo C.; Coetzee, Simon G.; Shen, Howard C.; Yang, Ally W.; Earp, Madalene A.; Yoder, Sean J.; Risch, Harvey; Chenevix-Trench, Georgia; Ramus, Susan J.; Phelan, Catherine M.; Coetzee, Gerhard A.; Noushmehr, Houtan; Hughes, Timothy R.; Sellers, Thomas A.; Goode, Ellen L.; Pharoah, Paul D.; Gayther, Simon A.; Monteiro, Alvaro N.A.; Chen, Y. Ann; Fridley, Brooke L.; Aben, Katja K.H.; Kiemeney, Lambertus A.; Anton-Culver, Hoda; Ziogas, Argyrios; Bruinsma, Fiona; Milne, Roger L.; Bandera, Elisa V.; Giles, Graham G.; Bean, Yukie T.; Pejovic, Tanja; Beckmann, Matthias W.; Hein, Alexander; Bjorge, Line; Fasching, Peter A.; Thomsen, Liv C.V.; Kopperud, Reidun K.; Bischof, Katharina; Bogdanova, Natalia; Doek, Thilo; Hillemanns, Peter; Brinton, Louise A.; Wentzensen, Nicolas; Yang, Hannah; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M.; Campbell, Ian G.; Southey, Melissa C.; Modugno, Francesmary; Carty, Karen; Glasspool, Rosalind; McNeish, Ian; Paul, James; Siddiqui, Nadeem; Chang-Claude, Jenny; Rudolph, Anja; Cook, Linda S.; Cramer, Daniel W.; Terry, Kathryn L.; Cunningham, Julie M.; Cybulski, Cezary; Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan; Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.; du Bois, Andreas; Harter, Philipp; Dicks, Ed; Song, Honglin; Doherty, Jennifer A.; Rossing, Mary Anne; Duerst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Goodman, Marc T.; Thompson, Pamela J.; Hasmad, Hanis N.; Teo, Soo-Hwang; Hildebrandt, Michelle A.T.; Wu, Xifeng; Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.; Iversen, Edwin S.; Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Walsh, Christine S.; Kelley, Joseph L.; Lambrechts, Diether; Lambrechts, Sandrina; Vergote, Ignace; Lee, Alice W.; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lundvall, Lene; Massuger, Leon F.AG.; van Altena, Anne M.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; Menon, Usha; Moysich, Kirsten B.; Ness, Roberta B.; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.; Pearce, Celeste L.; Wu, Anna H.; Permuth, Jennifer B.; Tsai, Ya-Yu; Tworoger, Shelley S.; Poole, Elizabeth M.; Rosen, Barry; Shu, Xiao-Ou; Shvetsov, Yurii B.; Wilkens, Lynne R.; Sieh, Weiva; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Thomsen, Lotte; Wang-Gohrke, Shan; Whittemore, Alice S.; Woo, Yin-Ling; Zheng, Wei; Berchuck, Andrew; Schildkraut, Joellen M.; Kelemen, Linda E.; Freedman, Matthew L. |
| Source: |
ISSN:0008-5472 ; ISSN:1538-7445 ; Cancer Research, vol. 79 (3), (467-481. |
| Publisher Information: |
American Association for Cancer Research |
| Publication Year: |
2019 |
| Subject Terms: |
Science & Technology; Life Sciences & Biomedicine; Oncology; GENOME-WIDE ASSOCIATION; DNA POLYMORPHISM; SKIN COLOR; GENE; TRANSCRIPTION; GWAS; IDENTIFICATION; MICROARRAYS; LANDSCAPE; VARIANTS; Base Sequence; Carcinoma; Ovarian Epithelial; Cell Cycle Proteins; Cell Line; Tumor; Chromosome Mapping; Chromosomes; Human; Pair 9; Cystadenocarcinoma; Serous; DNA; Neoplasm; DNA-Binding Proteins; Female; Genetic Predisposition to Disease |
| Description: |
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. ; sponsorship: We thank Alexandra Valle, Jiqiang Yao and Xueli Li for technical assistance and Anindya Dutta for helpful discussions. This work was supported by the following awards: NIH Genetic Association and Mechanisms in Oncology (GAME-ON) through NCI U19 (CA148112, to T.A. Sellers); K99/R00 (CA184415, to K. Lawrenson); and R01 (CA136924, to G.A. Coetzee), a grant from the Ovarian Cancer Research Foundation (258807, to S.A. Gayther), and in part by the Cancer Informatics, Proteomics and the Molecular Genomics Core Facilities at the Moffitt Cancer Center through its NCI CCSG grant (P30-CA76292, to T.A. Sellers). M.A. Buckley is an ARCS (Achievement Rewards for College Scientists) fellow and a recipient of the Ruth L. Kirschstein National Research Service Award ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://lirias.kuleuven.be/handle/123456789/634489; https://pubmed.ncbi.nlm.nih.gov/30487138 |
| DOI: |
10.1158/0008-5472.CAN-17-3864 |
| Availability: |
https://lirias.kuleuven.be/handle/123456789/634489; https://doi.org/10.1158/0008-5472.CAN-17-3864; https://pubmed.ncbi.nlm.nih.gov/30487138 |
| Rights: |
info:eu-repo/semantics/restrictedAccess ; intranet |
| Accession Number: |
edsbas.1B25D39B |
| Database: |
BASE |