Lu, Yingchang, Beeghly-Fadiel, Alicia, Wu, Lang, Guo, Xingyi, Li, Bingshan, Schildkraut, Joellen M., Im, Hae Kyung, Chen, Yian A., Permuth, Jennifer B., Reid, Brett M., Teer, Jamie K., Moysich, Kirsten B., Andrulis, Irene L., Anton-Culver, Hoda, Arun, Banu K., Bandera, Elisa V., Barkardottir, Rosa B., Barnes, Daniel R., Benitez, Javier, Bjorge, Line ORCID: 0000-0002-0240-2770, Brenton, James, Butzow, Ralf, Caldes, Trinidad, Caligo, Maria A., Campbell, Ian, Chang-Claude, Jenny, Claes, Kathleen B. M., Couch, Fergus J., Cramer, DanielW., Daly, Mary B., deFazio, Anna, Dennis, Joe, Diez, Orland, Domchek, Susan M., Doerk, Thilo, Easton, Douglas F., Eccles, Diana M., Fasching, Peter A., Fortner, Renee T., Fountzilas, George, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Giles, Graham G., Godwin, Andrew K., Goldgar, David E., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hamann, Ute, Heitz, Florian ORCID: 0000-0002-2412-0352, Hildebrandt, Michelle A. T., Hogdall, Claus K., Hollestelle, Antoinette, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna ORCID: 0000-0002-5650-0501, James, Paul ORCID: 0000-0002-4361-4657, Karlan, Beth Y., Kelemen, Linda E., Kiemeney, Lambertus A. ORCID: 0000-0002-2368-1326, Kjaer, Susanne K., Kwong, Ava ORCID: 0000-0002-6968-9489, Le, Nhu D., Leslie, Goska, Lesueur, Fabienne ORCID: 0000-0001-7404-4549, Levine, Douglas A., Mattiello, Amalia, May, Taymaa, McGuffog, Lesley, McNeish, Iain A., Merritt, Melissa A., Modugno, Francesmary, Montagna, Marco, Neuhausen, Susan L., Nevanlinna, Heli, Nielsen, Finn C., Nikitina-Zake, Liene, Nussbaum, Robert L., Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Hakan ORCID: 0000-0002-8794-9635, Osorio, Ana ORCID: 0000-0001-8124-3984, Park, Sue K., Parsons, Michael T., Peeters, Petra H. M., Pejovic, Tanja, Peterlongo, Paolo ORCID: 0000-0001-6951-6855, Phelan, Catherine M., Pujana, Miquel Angel, Ramus, Susan J., Rennert, Gad, Risch, Harvey, Rodriguez, Gustavo C., Rodriguez-Antona, Cristina ORCID: 0000-0001-8750-7338, Romieu, Isabelle, Rookus, Matti A., Rossing, Mary Anne, Rzepecka, Iwona K., Sandler, Dale P., Schmutzler, Rita K., Setiawan, Veronica W., Sharma, Priyanka, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Song, Honglin, Southey, Melissa C., Spurdle, Amanda B., Sutphen, Rebecca, Swerdlow, Anthony J., Teixeira, Manuel R., Teo, Soo H., Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E., Trichopoulou, Antonia, Tung, Nadine, Tworoger, Shelley S., van Rensburg, Elizabeth J., Vanderstichele, Adriaan, Vega, Ana, Edwards, Digna Velez, Webb, Penelope M., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Wolk, Alicja, Wu, Anna H., Yannoukakos, Drakoulis, Zorn, Kristin K., Gayther, Simon A., Antoniou, Antonis C., Berchuck, Andrew, Goode, Ellen L., Chenevix-Trench, Georgia ORCID: 0000-0002-1878-2587, Sellers, Thomas A., Pharoah, Paul D. P., Zheng, Wei and Long, Jirong ORCID: 0000-0002-7433-9766 (2018). A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk. Cancer Res., 78 (18). S. 5419 - 5431. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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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 x 10(-6), we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 x 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 x 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. (C) 2018 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lu, YingchangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beeghly-Fadiel, AliciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, LangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guo, XingyiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, BingshanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schildkraut, Joellen M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Im, Hae KyungUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, Yian A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Permuth, Jennifer B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reid, Brett M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teer, Jamie K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moysich, Kirsten B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anton-Culver, HodaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arun, Banu K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bandera, Elisa V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barkardottir, Rosa B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barnes, Daniel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bjorge, LineUNSPECIFIEDorcid.org/0000-0002-0240-2770UNSPECIFIED
Brenton, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Butzow, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldes, TrinidadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caligo, Maria A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chang-Claude, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claes, Kathleen B. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cramer, DanielW.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daly, Mary B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
deFazio, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dennis, JoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diez, OrlandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domchek, Susan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doerk, ThiloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eccles, Diana M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fasching, Peter A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fortner, Renee T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fountzilas, GeorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friedman, EitanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ganz, Patricia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garber, JudyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giles, Graham G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Godwin, Andrew K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldgar, David E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goodman, Marc T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greene, Mark H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gronwald, JacekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heitz, FlorianUNSPECIFIEDorcid.org/0000-0002-2412-0352UNSPECIFIED
Hildebrandt, Michelle A. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hogdall, Claus K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hollestelle, AntoinetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hulick, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huntsman, David G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imyanitov, Evgeny N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isaacs, ClaudineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakubowska, AnnaUNSPECIFIEDorcid.org/0000-0002-5650-0501UNSPECIFIED
James, PaulUNSPECIFIEDorcid.org/0000-0002-4361-4657UNSPECIFIED
Karlan, Beth Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelemen, Linda E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kiemeney, Lambertus A.UNSPECIFIEDorcid.org/0000-0002-2368-1326UNSPECIFIED
Kjaer, Susanne K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwong, AvaUNSPECIFIEDorcid.org/0000-0002-6968-9489UNSPECIFIED
Le, Nhu D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leslie, GoskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lesueur, FabienneUNSPECIFIEDorcid.org/0000-0001-7404-4549UNSPECIFIED
Levine, Douglas A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mattiello, AmaliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, TaymaaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McGuffog, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McNeish, Iain A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merritt, Melissa A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Modugno, FrancesmaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montagna, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhausen, Susan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nevanlinna, HeliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nielsen, Finn C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikitina-Zake, LieneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nussbaum, Robert L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offit, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olah, EdithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olopade, Olufunmilayo I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olson, Sara H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olsson, HakanUNSPECIFIEDorcid.org/0000-0002-8794-9635UNSPECIFIED
Osorio, AnaUNSPECIFIEDorcid.org/0000-0001-8124-3984UNSPECIFIED
Park, Sue K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parsons, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peeters, Petra H. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pejovic, TanjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peterlongo, PaoloUNSPECIFIEDorcid.org/0000-0001-6951-6855UNSPECIFIED
Phelan, Catherine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pujana, Miquel AngelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramus, Susan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rennert, GadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Risch, HarveyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez, Gustavo C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez-Antona, CristinaUNSPECIFIEDorcid.org/0000-0001-8750-7338UNSPECIFIED
Romieu, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rookus, Matti A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossing, Mary AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rzepecka, Iwona K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sandler, Dale P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Setiawan, Veronica W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sharma, PriyankaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sieh, WeivaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simard, JacquesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Singer, Christian F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Song, HonglinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southey, Melissa C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sutphen, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Swerdlow, Anthony J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teixeira, Manuel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Soo H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomassen, MadsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tischkowitz, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toland, Amanda E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trichopoulou, AntoniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tung, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tworoger, Shelley S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Rensburg, Elizabeth J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vanderstichele, AdriaanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vega, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edwards, Digna VelezUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Webb, Penelope M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weitzel, Jeffrey N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wentzensen, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
White, EmilyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolk, AlicjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Anna H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yannoukakos, DrakoulisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zorn, Kristin K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gayther, Simon A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antoniou, Antonis C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berchuck, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goode, Ellen L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDorcid.org/0000-0002-1878-2587UNSPECIFIED
Sellers, Thomas A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pharoah, Paul D. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zheng, WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Long, JirongUNSPECIFIEDorcid.org/0000-0002-7433-9766UNSPECIFIED
URN: urn:nbn:de:hbz:38-172855
DOI: 10.1158/0008-5472.CAN-18-0951
Journal or Publication Title: Cancer Res.
Volume: 78
Number: 18
Page Range: S. 5419 - 5431
Date: 2018
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1538-7445
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CORTICOTROPIN-RELEASING HORMONE; IN-VITRO FERTILIZATION; EXPRESSION; BREAST; LOCI; MULTIPLE; HOXB2; IDENTIFICATION; VARIANTS; GWASMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17285

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