Abstract
Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10-9) and 10p12 (rs1243180, P = 1.8 × 10-8) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
Original language | English (US) |
---|---|
Pages (from-to) | 362-370 |
Number of pages | 9 |
Journal | Nature genetics |
Volume | 45 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2013 |
ASJC Scopus subject areas
- Genetics
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In: Nature genetics, Vol. 45, No. 4, 04.2013, p. 362-370.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer
AU - Pharoah, Paul D.P.
AU - Tsai, Ya Yu
AU - Ramus, Susan J.
AU - Phelan, Catherine M.
AU - Goode, Ellen L.
AU - Lawrenson, Kate
AU - Buckley, Melissa
AU - Fridley, Brooke L.
AU - Tyrer, Jonathan P.
AU - Shen, Howard
AU - Weber, Rachel
AU - Karevan, Rod
AU - Larson, Melissa C.
AU - Song, Honglin
AU - Tessier, Daniel C.
AU - Bacot, François
AU - Vincent, Daniel
AU - Cunningham, Julie M.
AU - Dennis, Joe
AU - Dicks, Ed
AU - Aben, Katja K.
AU - Anton-Culver, Hoda
AU - Antonenkova, Natalia
AU - Armasu, Sebastian M.
AU - Baglietto, Laura
AU - Bandera, Elisa V.
AU - Beckmann, Matthias W.
AU - Birrer, Michael J.
AU - Bloom, Greg
AU - Bogdanova, Natalia
AU - Brenton, James D.
AU - Brinton, Louise A.
AU - Brooks-Wilson, Angela
AU - Brown, Robert
AU - Butzow, Ralf
AU - Campbell, Ian
AU - Carney, Michael E.
AU - Carvalho, Renato S.
AU - Chang-Claude, Jenny
AU - Chen, Y. Anne
AU - Chen, Zhihua
AU - Chow, Wong Ho
AU - Cicek, Mine S.
AU - Coetzee, Gerhard
AU - Cook, Linda S.
AU - Cramer, Daniel W.
AU - Cybulski, Cezary
AU - Dansonka-Mieszkowska, Agnieszka
AU - Despierre, Evelyn
AU - Doherty, Jennifer A.
AU - Dörk, Thilo
AU - Du Bois, Andreas
AU - Dürst, Matthias
AU - Eccles, Diana
AU - Edwards, Robert
AU - Ekici, Arif B.
AU - Fasching, Peter A.
AU - Fenstermacher, David
AU - Flanagan, James
AU - Gao, Yu Tang
AU - Garcia-Closas, Montserrat
AU - Gentry-Maharaj, Aleksandra
AU - Giles, Graham
AU - Gjyshi, Anxhela
AU - Gore, Martin
AU - Gronwald, Jacek
AU - Guo, Qi
AU - Halle, Mari K.
AU - Harter, Philipp
AU - Hein, Alexander
AU - Heitz, Florian
AU - Hillemanns, Peter
AU - Hoatlin, Maureen
AU - Høgdall, Estrid
AU - Høgdall, Claus K.
AU - Hosono, Satoyo
AU - Jakubowska, Anna
AU - Jensen, Allan
AU - Kalli, Kimberly R.
AU - Karlan, Beth Y.
AU - Kelemen, Linda E.
AU - Kiemeney, Lambertus A.
AU - Kjaer, Susanne Krüger
AU - Konecny, Gottfried E.
AU - Krakstad, Camilla
AU - Kupryjanczyk, Jolanta
AU - Lambrechts, Diether
AU - Lambrechts, Sandrina
AU - Le, Nhu D.
AU - Lee, Nathan
AU - Lee, Janet
AU - Leminen, Arto
AU - Lim, Boon Kiong
AU - Lissowska, Jolanta
AU - Lubiński, Jan
AU - Lundvall, Lene
AU - Lurie, Galina
AU - Massuger, Leon F.A.G.
AU - Matsuo, Keitaro
AU - McGuire, Valerie
AU - McLaughlin, John R.
AU - Menon, Usha
AU - Modugno, Francesmary
AU - Moysich, Kirsten B.
AU - Nakanishi, Toru
AU - Narod, Steven A.
AU - Ness, Roberta B.
AU - Nevanlinna, Heli
AU - Nickels, Stefan
AU - Noushmehr, Houtan
AU - Odunsi, Kunle
AU - Olson, Sara
AU - Orlow, Irene
AU - Paul, James
AU - Pejovic, Tanja
AU - Pelttari, Liisa M.
AU - Permuth-Wey, Jenny
AU - Pike, Malcolm C.
AU - Poole, Elizabeth M.
AU - Qu, Xiaotao
AU - Risch, Harvey A.
AU - Rodriguez-Rodriguez, Lorna
AU - Rossing, Mary Anne
AU - Rudolph, Anja
AU - Runnebaum, Ingo
AU - Rzepecka, Iwona K.
AU - Salvesen, Helga B.
AU - Schwaab, Ira
AU - Severi, Gianluca
AU - Shen, Hui
AU - Shridhar, Vijayalakshmi
AU - Shu, Xiao Ou
AU - Sieh, Weiva
AU - Southey, Melissa C.
AU - Spellman, Paul
AU - Tajima, Kazuo
AU - Teo, Soo Hwang
AU - Terry, Kathryn L.
AU - Thompson, Pamela J.
AU - Timorek, Agnieszka
AU - Tworoger, Shelley S.
AU - Van Altena, Anne M.
AU - Van Den Berg, David
AU - Vergote, Ignace
AU - Vierkant, Robert A.
AU - Vitonis, Allison F.
AU - Wang-Gohrke, Shan
AU - Wentzensen, Nicolas
AU - Whittemore, Alice S.
AU - Wik, Elisabeth
AU - Winterhoff, Boris
AU - Woo, Yin Ling
AU - Wu, Anna H.
AU - Yang, Hannah P.
AU - Zheng, Wei
AU - Ziogas, Argyrios
AU - Zulkifli, Famida
AU - Goodman, Marc T.
AU - Hall, Per
AU - Easton, Douglas F.
AU - Pearce, Celeste L.
AU - Berchuck, Andrew
AU - Chenevix-Trench, Georgia
AU - Iversen, Edwin
AU - Monteiro, Alvaro N.A.
AU - Gayther, Simon A.
AU - Schildkraut, Joellen M.
AU - Sellers, Thomas A.
N1 - Funding Information: We thank all the individuals who took part in this study and all the researchers, clinicians and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note). The COGS project is funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were supported in part by the Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about The Cancer Genome Atlas (TCGA) and the investigators and institutions who constitute the TCGA research network can be found on the website (see URLs).
PY - 2013/4
Y1 - 2013/4
N2 - Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10-9) and 10p12 (rs1243180, P = 1.8 × 10-8) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
AB - Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10-9) and 10p12 (rs1243180, P = 1.8 × 10-8) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
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U2 - 10.1038/ng.2564
DO - 10.1038/ng.2564
M3 - Article
C2 - 23535730
AN - SCOPUS:84875707717
SN - 1061-4036
VL - 45
SP - 362
EP - 370
JO - Nature genetics
JF - Nature genetics
IS - 4
ER -