TY - JOUR

T1 - Identification of 22 susceptibility loci associated with testicular germ cell tumors

AU - Pluta, John

AU - Pyle, Louise C.

AU - Nead, Kevin T.

AU - Wilf, Rona

AU - Li, Mingyao

AU - Mitra, Nandita

AU - Weathers, Benita

AU - D’Andrea, Kurt

AU - Almstrup, Kristian

AU - Anson-Cartwright, Lynn

AU - Benitez, Javier

AU - Brown, Christopher D.

AU - Chanock, Stephen

AU - Chen, Chu

AU - Cortessis, Victoria K.

AU - Ferlin, Alberto

AU - Foresta, Carlo

AU - Gamulin, Marija

AU - Gietema, Jourik A.

AU - Grasso, Chiara

AU - Greene, Mark H.

AU - Grotmol, Tom

AU - Hamilton, Robert J.

AU - Haugen, Trine B.

AU - Hauser, Russ

AU - Hildebrandt, Michelle A.T.

AU - Johnson, Matthew E.

AU - Karlsson, Robert

AU - Kiemeney, Lambertus A.

AU - Lessel, Davor

AU - Lothe, Ragnhild A.

AU - Loud, Jennifer T.

AU - Loveday, Chey

AU - Martin-Gimeno, Paloma

AU - Meijer, Coby

AU - Nsengimana, Jérémie

AU - Quinn, David I.

AU - Rafnar, Thorunn

AU - Ramdas, Shweta

AU - Richiardi, Lorenzo

AU - Skotheim, Rolf I.

AU - Stefansson, Kari

AU - Turnbull, Clare

AU - Vaughn, David J.

AU - Wiklund, Fredrik

AU - Wu, Xifeng

AU - Yang, Daphne

AU - Zheng, Tongzhang

AU - Wells, Andrew D.

AU - Rajpert-De Meyts, Ewa

AU - The Testicular Cancer Consortium

N1 - Funding Information: We thank the participants in the testicular cancer germ cell studies around the world that contributed to this study. We would like to thank Emily Carver and David Ruggieri of IMS for conducting data harmonization, the Center for Applied Genomics at CHOP for technical assistance, specifically Renata Pellagrino, PhD, Laboratory Technical Director, and Drs. Riko and Sohei Kitazawa of Ehime University School of Medicine, Japan, for generously sharing the TCAM2 cell line for this study. J.B. and P.M.-G. thank Beatriz Paumard-Hernandez, the Spanish Germ Cell Cancer Group, and all the collaborating hospitals for their help and support. D.T.B. and J.N. thank Louise Parkinson, Katie Hasler, Mark Harland, and Tracey Mell for their contribution in the Leeds Testicular Cancer Study. A.F. would like to thank Dr. Maria Santa Rocca for technical assistance. J.A.G. and C.M. would like to thank Nynke Zwart and Gerrie Steursma for their contributions to the study. A.D.W. and S.F.A.G. acknowledge Elisabetta Manduchi for establishing the promoter Capture-C pipeline. K.A. and E.R.-DeM. would like to thank Marlene Dalgaard, Daniel Edsgärd, Niels Weinhold, and Ramneek Gupta for their contributions to data collection and analysis in the original Danish GWAS. C.C. and S.M. S. are grateful to David R. Doody, Martha Shellenberger, and the ATLAS study participants for their contributions. R.A.L. and R.I.S. are grateful to Professor emerita Sophie D. Fosså for inclusion of patients to the Oslo University Hospital series. R.H. and T.Z. would like to thank the cooperation of 28 Connecticut hospitals, the Connecticut Tumor Registry, the Connecticut Department of Public Health, Massachusetts Department of Public Health, and Rajni Mehta from the Yale Comprehensive Cancer Center. PAK, D.J. V. and K.L.N. would like to thank Linda Jacobs and Donna Pucci for the contributions to participant recruitment and the study participants from the University of Pennsylvania. The Testicular Cancer Consortium is supported by National Institutes of Health (NIH) grant U01 CA164947 to KLN, PAK and SMS. The Penn GWAS was supported by the Abramson Cancer Center at the University of Pennsylvania (P30 CA016520) and NIH grant CA114478 to K.L.N. and P.A.K. L.C.P. was supported by NIH training grants T32 GM008638 and KL2 TR001879. This research was supported in part by grants R01 CA102042 to VKC, 03-00174-30021 and 99-0050-V-10260 from the California Cancer Research Program, and awards from the Robert E. and May R. Wright Foundation and the Whittier Foundation. The MDACC TGCT study (MATH) was supported by the MD Anderson Cancer Center Support Grant (P30 CA016672). A portion of this work was supported by the Intramural Research Program of the National Cancer Institute (S.C., M. G., J.T.L., K.A.M.) and by a support services contract HHSN26120130003C with IMS, Inc. The Seattle TGCT study (C.C., S.M.S.) was supported by NIH grants R01 CA085914 and contracts CN-67009 and PC-35142, and Fred Hutchinson Cancer Research Center institutional funds. T.Z. and R.H. were supported by NIH grant R01 CA104786. S.F.A.G. is supported by NIH R01 HG010067 and the Daniel B. Burke Endowed Chair for Diabetes Research. The Danish GWAS (K.A., E.R.-deM.) was supported by Villum Kann Rasmussen Foundation, a NABIIT grant from the Danish Strategic Research Council, the Novo Nordisk Foundation, the Danish Cancer Society, and the Danish Childhood Cancer Foundation. P.M.-G. is supported by the Spanish Network on Rare Diseases (CIBERER). JB’s laboratory is partially funded by a grant from the Spanish Health Ministry: FIS PI16/00440 with FEDER funds; from the EU H2020 Rf.634935. D.T.B. and J.N. were supported by Cancer Research UK Programme Award C588/A19167. The UK Testicular Cancer Study (DTB, JN, CL, CT) was supported by the Institute of Cancer Research, Cancer Research UK and made use of control data generated by the Wellcome Trust Case Control Consortium (WTCCC). C.T. and C.L. are supported by the Move-mber foundation. C.G. and L.R. are partially supported by the Piedmont Region and the Italian Ministry for Education, University and Research (Ministero dell’Istruzione, dell’Università e della Ricerca—MIUR) under the programme “Dipartimenti di Eccellenza 2018–2022”. C.G. was supported by Fondazione Umberto Veronesi. The Norwegian/ Swedish TGCT study (T.G., T.B.H., R.K., F.W.) was supported by the Norwegian Cancer Society (grants number 418975–71081–PR-2006-0387 and PK01-2007-0375); the Nordic Cancer Union (grant number S-12/07) and the Swedish Cancer Society (grant numbers 2008/708, 2010/808, 2011/484, and CAN2012/823). R.H. was supported by the Dell’Elce Family Fund and Princess Margaret Cancer Foundation. The laboratory of D. Lessel is supported by the Deutsche Krebshilfe grant (70113348). R.A.L. and R.I.S. were supported by grants from the Norwegian Cancer Society and the South-Eastern Norway Regional Health Authority. K.M.N. is a Cancer Prevention Research Institute of Texas (CPRIT) Scholar in Cancer Research. Publisher Copyright: © 2021, The Author(s).

PY - 2021

Y1 - 2021

N2 - Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.

AB - Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.

U2 - 10.1038/s41467-021-24334-y

DO - 10.1038/s41467-021-24334-y

M3 - Journal article

C2 - 34301922

AN - SCOPUS:85112280158

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4487

ER -