A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24.

Publication Type:

Journal Article

Authors:

Goode, Ellen L; Chenevix-Trench, Georgia; Song, Honglin; Ramus, Susan J; Notaridou, Maria; Lawrenson, Kate; Widschwendter, Martin; Vierkant, Robert A; Larson, Melissa C; Kjaer, Susanne K; Birrer, Michael J; Berchuck, Andrew; Schildkraut, Joellen; Tomlinson, Ian; Kiemeney, Lambertus A; Cook, Linda S; Gronwald, Jacek; Garcia-Closas, Montserrat; Gore, Martin E; Campbell, Ian; Whittemore, Alice S; Sutphen, Rebecca; Phelan, Catherine; Anton-Culver, Hoda; Pearce, Celeste Leigh; Lambrechts, Diether; Rossing, Mary Anne; Chang-Claude, Jenny; Moysich, Kirsten B; Goodman, Marc T; Dörk, Thilo; Nevanlinna, Heli; Ness, Roberta B; Rafnar, Thorunn; Hogdall, Claus; Hogdall, Estrid; Fridley, Brooke L; Cunningham, Julie M; Sieh, Weiva; McGuire, Valerie; Godwin, Andrew K; Cramer, Daniel W; Hernandez, Dena; Levine, Douglas; Lu, Karen; Iversen, Edwin S; Palmieri, Rachel T; Houlston, Richard; van Altena, Anne M; Aben, Katja K H; Massuger, Leon F A G; Brooks-Wilson, Angela; Kelemen, Linda E; Le, Nhu D; Jakubowska, Anna; Lubinski, Jan; Medrek, Krzysztof; Stafford, Anne; Easton, Douglas F; Tyrer, Jonathan; Bolton, Kelly L; Harrington, Patricia; Eccles, Diana; Chen, Ann; Molina, Ashley N; Davila, Barbara N; Arango, Hector; Tsai, Ya-Yu; Chen, Zhihua; Risch, Harvey A; McLaughlin, John; Narod, Steven A; Ziogas, Argyrios; Brewster, Wendy; Gentry-Maharaj, Aleksandra; Menon, Usha; Wu, Anna H; Stram, Daniel O; Pike, Malcolm C; Beesley, Jonathan; Webb, Penelope M; Chen, Xiaoqing; Ekici, Arif B; Thiel, Falk C; Beckmann, Matthias W; Yang, Hannah; Wentzensen, Nicolas; Lissowska, Jolanta; Fasching, Peter A; Despierre, Evelyn; Amant, Frederic; Vergote, Ignace; Doherty, Jennifer A; Hein, Rebecca; Wang-Gohrke, Shan; Lurie, Galina; Carney, Michael E; Thompson, Pamela J; Runnebaum, Ingo; Hillemanns, Peter; Dürst, Matthias; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Butzow, Ralf; Heikkinen, Tuomas; Stefansson, Kari; Sulem, Patrick; Besenbacher, Sören; Sellers, Thomas A; Gayther, Simon A; Pharoah, Paul D P

Source:

Nature genetics, Volume 42, Issue 10, p.874-9 (2010)

Keywords:

2010, Case-Control Studies, Center-Authored Paper, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 8, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Homeodomain Proteins, Humans, Ovarian Neoplasms, Ovary, Phosphoproteins, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-myb, Public Health Sciences Division, Shared Resources, Specimen Processing Core Facility, Tumor Markers, Biological

Abstract:

Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P ≤ 10⁻⁴) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ≤ 5 × 10⁻⁸ (8q24, P = 8.0 × 10⁻¹⁵ and 2q31, P = 3.8 × 10⁻¹⁴) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10⁻⁸ and 17q21, P = 1.4 × 10⁻⁷). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.