Journal Article

DKFZ-2018-02313

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

Lu, Y. ; Beeghly-Fadiel, A. ; Wu, L. ; Guo, X. ; Li, B. ; Schildkraut, J. M. ; Im, H. K. ; Chen, Y. A. ; Permuth, J. B. ; Reid, B. M. ; Teer, J. K. ; Moysich, K. B. ; Andrulis, I. L. ; Anton-Culver, H. ; Arun, B. K. ; Bandera, E. V. ; Barkardottir, R. B. ; Barnes, D. R. ; Benitez, J. ; Bjorge, L. ; Brenton, J. ; Butzow, R. ; Caldes, T. ; Caligo, M. A. ; Campbell, I. ; Chang-Claude, J.DKFZ* ; Claes, K. B. M. ; Couch, F. J. ; Cramer, D. W. ; Daly, M. B. ; deFazio, A. ; Dennis, J. ; Diez, O. ; Domchek, S. M. ; Dörk, T. ; Easton, D. F. ; Eccles, D. M. ; Fasching, P. A. ; Turzanski-Fortner, R.DKFZ* ; Fountzilas, G. ; Friedman, E. ; Ganz, P. A. ; Garber, J. ; Giles, G. G. ; Godwin, A. K. ; Goldgar, D. E. ; Goodman, M. T. ; Greene, M. H. ; Gronwald, J. ; Hamann, U.DKFZ* ; Heitz, F. ; Hildebrandt, M. A. T. ; Høgdall, C. K. ; Hollestelle, A. ; Hulick, P. J. ; Huntsman, D. G. ; Imyanitov, E. N. ; Isaacs, C. ; Jakubowska, A. ; James, P. ; Karlan, B. Y. ; Kelemen, L. E. ; Kiemeney, L. A. ; Kjaer, S. K. ; Kwong, A. ; Le, N. D. ; Leslie, G. ; Lesueur, F. ; Levine, D. A. ; Mattiello, A. ; May, T. ; McGuffog, L. ; McNeish, I. A. ; Merritt, M. A. ; Modugno, F. ; Montagna, M. ; Neuhausen, S. L. ; Nevanlinna, H. ; Nielsen, F. C. ; Nikitina-Zake, L. ; Nussbaum, R. L. ; Offit, K. ; Olah, E. ; Olopade, O. I. ; Olson, S. H. ; Olsson, H. ; Osorio, A. ; Park, S. K. ; Parsons, M. T. ; Peeters, P. H. M. ; Pejovic, T. ; Peterlongo, P. ; Phelan, C. M. ; Pujana, M. A. ; Ramus, S. J. ; Rennert, G. ; Risch, H. ; Rodriguez, G. C. ; Rodríguez-Antona, C. ; Romieu, I. ; Rookus, M. A. ; Rossing, M. A. ; Rzepecka, I. K. ; Sandler, D. P. ; Schmutzler, R. K. ; Setiawan, V. W. ; Sharma, P. ; Sieh, W. ; Simard, J. ; Singer, C. F. ; Song, H. ; Southey, M. C. ; Spurdle, A. B. ; Sutphen, R. ; Swerdlow, A. J. ; Teixeira, M. R. ; Teo, S. H. ; Thomassen, M. ; Tischkowitz, M. ; Toland, A. E. ; Trichopoulou, A. ; Tung, N. ; Tworoger, S. S. ; van Rensburg, E. J. ; Vanderstichele, A. ; Vega, A. ; Edwards, D. V. ; Webb, P. M. ; Weitzel, J. N. ; Wentzensen, N. ; White, E. ; Wolk, A. ; Wu, A. H. ; Yannoukakos, D. ; Zorn, K. K. ; Gayther, S. A. ; Antoniou, A. C. ; Berchuck, A. ; Goode, E. L. ; Chenevix-Trench, G. ; Sellers, T. A. ; Pharoah, P. D. P. ; Zheng, W. ; Long, J.

2018
AACR Philadelphia, Pa.

This record in other databases:  

Please use a persistent id in citations: doi:10.1158/0008-5472.CAN-18-0951

Abstract: Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

---

Contributing Institute(s):

1. C020 Epidemiologie von Krebs (C020)
2. Molekulargenetik des Mammakarzinoms (B072)

Research Program(s):

1. 319H - Addenda (POF3-319H) (POF3-319H)

Appears in the scientific report 2018

---

Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

---