Chey Loveday1, Philip Law1, Kevin Litchfield1, Max Levy1, Amy Holroyd1, Peter Broderick1, Zsofia Kote-Jarai1, Alison M Dunning2, Kenneth Muir3, Julian Peto4, Rosalind Eeles5, Douglas F Easton6, Darshna Dudakia1, Nick Orr7, Nora Pashayan8, Alison Reid9, Robert A Huddart10, Richard S Houlston1, Clare Turnbull11. 1. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. 2. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. 3. Division of Health Sciences, Warwick Medical School, Warwick University, Warwick, UK; Institute of Population Health, University of Manchester, Manchester, UK. 4. Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. 5. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK. 6. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 7. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK. 8. Department of Applied Health Research, University College London, London, UK. 9. Academic Uro-oncology Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK. 10. Academic Radiotherapy Unit, Institute of Cancer Research, Sutton, Surrey, UK. 11. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; William Harvey Research Institute, Queen Mary University, London, UK; Department of Clinical Genetics, Guys and St Thomas NHS Foundation Trust, London, UK; Public Health England, National Cancer Registration and Analysis Service, London, UK. Electronic address: clare.turnbull@icr.ac.uk.
Abstract
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84-100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene. PATIENT SUMMARY: To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general.
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84-100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene. PATIENT SUMMARY: To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general.
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