Identification of 22 susceptibility loci associated with testicular germ cell tumors

John Pluta; Louise C Pyle; Kevin T Nead; Rona Wilf; Mingyao Li; Nandita Mitra; Benita Weathers; Kurt D'Andrea; Kristian Almstrup; Lynn Anson-Cartwright; Javier Benitez; Christopher D Brown; Stephen Chanock; Chu Chen; Victoria K Cortessis; Alberto Ferlin; Carlo Foresta; Marija Gamulin; Jourik A Gietema; Chiara Grasso; Mark H Greene; Tom Grotmol; Robert J Hamilton; Trine B Haugen; Russ Hauser; Michelle A T Hildebrandt; Matthew E Johnson; Robert Karlsson; Lambertus A Kiemeney; Davor Lessel; Ragnhild A Lothe; Jennifer T Loud; Chey Loveday; Paloma Martin-Gimeno; Coby Meijer; Jérémie Nsengimana; David I Quinn; Thorunn Rafnar; Shweta Ramdas; Lorenzo Richiardi; Rolf I Skotheim; Kari Stefansson; Clare Turnbull; David J Vaughn; Fredrik Wiklund; Xifeng Wu; Daphne Yang; Tongzhang Zheng; Andrew D Wells; Struan F A Grant; Ewa Rajpert-De Meyts; Stephen M Schwartz; D Timothy Bishop; Katherine A McGlynn; Peter A Kanetsky; Katherine L Nathanson; Testicular Cancer Consortium

doi:10.1038/s41467-021-24334-y

Identification of 22 susceptibility loci associated with testicular germ cell tumors

Nat Commun. 2021 Jul 23;12(1):4487. doi: 10.1038/s41467-021-24334-y.

Authors

John Pluta¹, Louise C Pyle², Kevin T Nead³, Rona Wilf¹, Mingyao Li⁴, Nandita Mitra⁴, Benita Weathers¹, Kurt D'Andrea¹, Kristian Almstrup⁵, Lynn Anson-Cartwright⁶, Javier Benitez⁷, Christopher D Brown⁸, Stephen Chanock⁹, Chu Chen¹⁰, Victoria K Cortessis¹¹, Alberto Ferlin¹², Carlo Foresta¹³, Marija Gamulin¹⁴, Jourik A Gietema¹⁵, Chiara Grasso¹⁶, Mark H Greene⁹, Tom Grotmol¹⁷, Robert J Hamilton⁶, Trine B Haugen¹⁸, Russ Hauser¹⁹, Michelle A T Hildebrandt²⁰, Matthew E Johnson^{2

21}, Robert Karlsson²², Lambertus A Kiemeney²³, Davor Lessel²⁴, Ragnhild A Lothe^{25

26}, Jennifer T Loud⁹, Chey Loveday²⁷, Paloma Martin-Gimeno⁷, Coby Meijer¹⁵, Jérémie Nsengimana²⁸, David I Quinn²⁹, Thorunn Rafnar³⁰, Shweta Ramdas⁸, Lorenzo Richiardi¹⁶, Rolf I Skotheim^{25

31}, Kari Stefansson³⁰, Clare Turnbull^{26

32}, David J Vaughn^{33

34}, Fredrik Wiklund²², Xifeng Wu³⁵, Daphne Yang¹, Tongzhang Zheng³⁶, Andrew D Wells^{21

37}, Struan F A Grant^{2

8

21}, Ewa Rajpert-De Meyts⁵, Stephen M Schwartz¹⁰, D Timothy Bishop³⁸, Katherine A McGlynn⁹, Peter A Kanetsky³⁹, Katherine L Nathanson^{40

41}; Testicular Cancer Consortium

Collaborator

Testicular Cancer Consortium:
Christian Kubisch

Affiliations

¹ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³ Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark.
⁶ Department of Surgery (Urology), University of Toronto and The Princess Margaret Cancer Centre, Toronto, ON, Canada.
⁷ Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
⁸ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Bethesda, MD, USA.
¹⁰ Program in Epidemiology, Fred Hutchinson Cancer Research Center; Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹¹ Departments of Preventive Medicine and Obstetrics and Gynecology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
¹² Unit of Endocrinology and Metabolism, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹³ Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy.
¹⁴ Department of Oncology, Division of Medical Oncology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia.
¹⁵ Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
¹⁶ Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and CPO-Piemonte, Turin, Italy.
¹⁷ Department of Research, Cancer Registry of Norway, Oslo, Norway.
¹⁸ Faculty of Health Sciences, OsloMet-Oslo Metropolitan University, Oslo, Norway.
¹⁹ Department of Environmental Health, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁰ Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²¹ Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²³ Radboud University Medical Center, Nijmegen, Netherlands.
²⁴ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁵ Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
²⁶ Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
²⁷ Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.
²⁸ Biostatistics Research Group, Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK.
²⁹ Division of Oncology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
³⁰ deCODE Genetics/Amgen, Reykjavik, Iceland.
³¹ Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
³² William Harvey Research Institute, Queen Mary University, London, UK.
³³ Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁴ Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁵ School of Public Health, Zhejiang University, Zhejiang, China.
³⁶ Department of Epidemiology, Brown School of Public Health, Brown University, Providence, RI, USA.
³⁷ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁸ Department of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
³⁹ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁴⁰ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. knathans@upenn.edu.
⁴¹ Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. knathans@upenn.edu.

Abstract

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 95^th 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cell Line, Tumor
Chromosome Mapping
Gene Regulatory Networks / genetics
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study / methods*
Genotype
Humans
Linkage Disequilibrium
Male
Meta-Analysis as Topic
Neoplasms, Germ Cell and Embryonal / genetics*
Neoplasms, Germ Cell and Embryonal / metabolism
Polymorphism, Single Nucleotide*
Protein Interaction Maps / genetics
Testicular Neoplasms / genetics*
Testicular Neoplasms / metabolism

Abstract

Publication types

MeSH terms

Grants and funding