Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology.
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Authors
Loveday, Chey
Law, Philip
Litchfield, Kevin
Levy, Max
Holroyd, Amy
Broderick, Peter
Kote-Jarai, Zsofia
Dunning, Alison M
Muir, Kenneth
Peto, Julian
Eeles, Rosalind
Easton, Douglas F
Dudakia, Darshna
Orr, Nick
Pashayan, Nora
UK Testicular Cancer Collaboration, The PRACTICAL Consortium
Reid, Alison
Huddart, Robert A
Houlston, Richard S
Turnbull, Clare
Publication Date
2018-09Journal Title
Eur Urol
ISSN
0302-2838
Publisher
Elsevier BV
Volume
74
Issue
3
Pages
248-252
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Loveday, C., Law, P., Litchfield, K., Levy, M., Holroyd, A., Broderick, P., Kote-Jarai, Z., et al. (2018). Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology.. Eur Urol, 74 (3), 248-252. https://doi.org/10.1016/j.eururo.2018.05.036
Abstract
UNLABELLED: 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.
Keywords
Familial, GWAS, Genetics, Polygenic risk score, Testicular germ cell tumour, Biomarkers, Tumor, Case-Control Studies, Environment, Genetic Predisposition to Disease, Genome-Wide Association Study, Heredity, Humans, Life Style, Male, Multifactorial Inheritance, Neoplasms, Germ Cell and Embryonal, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Testicular Neoplasms
Sponsorship
Cancer Research UK (16565)
National Cancer Institute (U19CA148537)
Cancer Research UK (A16563)
Cancer Research UK (A10118)
Identifiers
External DOI: https://doi.org/10.1016/j.eururo.2018.05.036
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280643
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