Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
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Ferlay, J. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893–2917 (2010).
Hall, J.M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).
Walsh, T. et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc. Natl. Acad. Sci. USA 108, 18032–18037 (2011).
Lynch, H.T. et al. Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). II. Biomarker studies. Cancer 56, 939–951 (1985).
Lynch, H.T., Conway, T. & Lynch, J. Hereditary ovarian cancer. Pedigree studies, Part II. Cancer Genet. Cytogenet. 53, 161–183 (1991).
Boyd, J. & Rubin, S.C. Hereditary ovarian cancer: molecular genetics and clinical implications. Gynecol. Oncol. 64, 196–206 (1997).
Narod, S.A. et al. Hereditary and familial ovarian cancer in southern Ontario. Cancer 74, 2341–2346 (1994).
Risch, H.A. et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J. Natl. Cancer Inst. 98, 1694–1706 (2006).
Song, H. et al. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat. Genet. 41, 996–1000 (2009).
Goode, E.L. et al. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat. Genet. 42, 874–879 (2010).
Bolton, K.L. et al. Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat. Genet. 42, 880–884 (2010).
Pharoah, P.D. et al. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. Nat. Genet. 45, 362–370 (2013).
Bojesen, S.E. et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat. Genet. 45, 371–384 (2013).
Permuth-Wey, J. et al. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Nat. Commun. 4, 1627 (2013).
Couch, F.J. et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet. 9, e1003212 (2013).
Chen, K. et al. Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women. Nat. Commun. 5, 4682 (2014).
Kuchenbaecker, K.B. et al. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat. Genet. 47, 164–171 (2015).
Vaughan, S. et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat. Rev. Cancer 11, 719–725 (2011).
Risch, H.A., Marrett, L.D., Jain, M. & Howe, G.R. Differences in risk factors for epithelial ovarian cancer by histologic type. Results of a case-control study. Am. J. Epidemiol. 144, 363–372 (1996).
Pearce, C.L. et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol. 13, 385–394 (2012).
Faber, M.T. et al. Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies. Cancer Causes Control 24, 989–1004 (2013).
Alsop, K. et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J. Clin. Oncol. 30, 2654–2663 (2012).
Köbel, M. et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med. 5, e232 (2008).
Gilks, C.B. et al. Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum. Pathol. 39, 1239–1251 (2008).
Tavassoulu,, F.A. & Devilee, P. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Breast and Female Genital Organs (IARC Press, 2003).
Seidman, J.D., Kurman, R.J. & Ronnett, B.M. Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am. J. Surg. Pathol. 27, 985–993 (2003).
Ronnett, B.M. et al. Mucinous borderline ovarian tumors: points of general agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior. Hum. Pathol. 35, 949–960 (2004).
Ronnett, B.M. et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei.” Am. J. Surg. Pathol. 19, 1390–1408 (1995).
Lee, K.R. & Young, R.H. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am. J. Surg. Pathol. 27, 281–292 (2003).
Yemelyanova, A.V., Vang, R., Judson, K., Wu, L.S. & Ronnett, B.M. Distinction of primary and metastatic mucinous tumors involving the ovary: analysis of size and laterality data by primary site with reevaluation of an algorithm for tumor classification. Am. J. Surg. Pathol. 32, 128–138 (2008).
Hart, W.R. Mucinous tumors of the ovary: a review. Int. J. Gynecol. Pathol. 24, 4–25 (2005).
Cuatrecasas, M., Villanueva, A., Matias-Guiu, X. & Prat, J. K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases. Cancer 79, 1581–1586 (1997).
Pieretti, M. et al. Heterogeneity of ovarian cancer: relationships among histological group, stage of disease, tumor markers, patient characteristics, and survival. Cancer Invest. 20, 11–23 (2002).
Ichikawa, Y. et al. Mutation of K-ras protooncogene is associated with histological subtypes in human mucinous ovarian tumors. Cancer Res. 54, 33–35 (1994).
Feeley, K.M. & Wells, M. Precursor lesions of ovarian epithelial malignancy. Histopathology 38, 87–95 (2001).
Heinzelmann-Schwarz, V.A. et al. A distinct molecular profile associated with mucinous epithelial ovarian cancer. Br. J. Cancer 94, 904–913 (2006).
Marquez, R.T. et al. Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon. Clin. Cancer Res. 11, 6116–6126 (2005).
Vogelstein, B. et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319, 525–532 (1988).
Shen, H. et al. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nat. Commun. 4, 1628 (2013).
Kelemen, L.E. & Kobel, M. Mucinous carcinomas of the ovary and colorectum: different organ, same dilemma. Lancet Oncol. 12, 1071–1080 (2011).
Chen, J.M., Ferec, C. & Cooper, D.N. A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3′ UTR variants. Hum. Genet. 120, 301–333 (2006).
The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).
The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).
Brown, C.D., Mangravite, L.M. & Engelhardt, B.E. Integrative modeling of eQTLs and cis-regulatory elements suggests mechanisms underlying cell type specificity of eQTLs. PLoS Genet. 9, e1003649 (2013).
Li, H., Huang, C.J. & Choo, K.B. Expression of homeobox genes in cervical cancer. Gynecol. Oncol. 84, 216–221 (2002).
Tabuse, M. et al. Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells. Mol. Cancer 10, 60 (2011).
Laury, A.R. et al. PAX8 reliably distinguishes ovarian serous tumors from malignant mesothelioma. Am. J. Surg. Pathol. 34, 627–635 (2010).
Laury, A.R. et al. A comprehensive analysis of PAX8 expression in human epithelial tumors. Am. J. Surg. Pathol. 35, 816–826 (2011).
Cheung, H.W. et al. Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer. Proc. Natl. Acad. Sci. USA 108, 12372–12377 (2011).
Muratovska, A., Zhou, C., He, S., Goodyer, P. & Eccles, M.R. Paired-Box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene 22, 7989–7997 (2003).
Di Palma, T., Lucci, V., de Cristofaro, T., Filippone, M.G. & Zannini, M. A role for PAX8 in the tumorigenic phenotype of ovarian cancer cells. BMC Cancer 14, 292 (2014).
Duggal, P. et al. Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann. Intern. Med. 158, 235–245 (2013).
Ochi, H. et al. IL-28B predicts response to chronic hepatitis C therapy—fine-mapping and replication study in Asian populations. J. Gen. Virol. 92, 1071–1081 (2011).
Key, F.M. et al. Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon λ4 (IFNL4). PLoS Genet. 10, e1004681 (2014).
Urban, T.J. et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 52, 1888–1896 (2010).
Pejovic, T. Genetic changes in ovarian cancer. Ann. Med. 27, 73–78 (1995).
Houlston, R.S. et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat. Genet. 42, 973–977 (2010).
Michailidou, K. et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat. Genet. 45, 353–361 (2013).
Eeles, R.A. et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat. Genet. 45, 385–391 (2013).
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
Permuth-Wey, J. et al. LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer. Cancer Res. 71, 3896–3903 (2011).
Delaneau, O., Marchini, J. & Zagury, J.F. A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2012).
Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
Xing, G., Lin, C.Y., Wooding, S.P. & Xing, C. Blindly using Wald's test can miss rare disease-causal variants in case-control association studies. Ann. Hum. Genet. 76, 168–177 (2012).
Coetzee, S.G. et al. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci. Hum. Mol. Genet. doi:10.1093/hmg/ddv101 (24 March 2015).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Li, Q. et al. Integrative eQTL-based analyses reveal the biology of breast cancer risk loci. Cell 152, 633–641 (2013).
Li, Q. et al. Expression QTL–based analyses reveal candidate causal genes and loci across five tumor types. Hum. Mol. Genet. 23, 5294–5302 (2014).
Kunzmann, R. & Holzel, F. Karyotype alterations in human ovarian carcinoma cells during long-term cultivation and nude mouse passage. Cancer Genet. Cytogenet. 28, 201–212 (1987).
Li, N.F. et al. A modified medium that significantly improves the growth of human normal ovarian surface epithelial (OSE) cells in vitro. Lab. Invest. 84, 923–931 (2004).
Pomerantz, M.M. et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat. Genet. 41, 882–884 (2009).
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 223175–HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium (OCAC) 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 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 consortium website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas (TCGA) Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about TCGA and the investigators and institutions who constitute the TCGA research network can be found on the project website (see URLs).
The author declare no competing financial interests.
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The Ovarian Cancer Association Consortium., Kelemen, L., Lawrenson, K. et al. Genome-wide significant risk associations for mucinous ovarian carcinoma. Nat Genet 47, 888–897 (2015). https://doi.org/10.1038/ng.3336
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