Testicular germ cell tumour (TGCT), the most common cancer in young men, has a significant heritable basis that has long raised questions as to the existence of underlying major high-penetrance susceptibility gene(s). To determine the contribution of rare gene mutations to the inherited risk of TGCT, we analysed germline whole-exome data for 919 TGCT cases and 1609 cancer-free controls. We compared frequencies between TGCT cases and controls of rare (<1%) and low-frequency (1-5%) coding variants (1) individually and (2) collapsed at the gene level via burden testing (T1, disruptive; T2, all deleterious; and T3, all nonsynonymous) using Fisher's exact test with Bonferroni correction of significance thresholds. No individual variant or individual gene showed a significant association with TGCT after correction for multiple testing. In the largest whole-exome sequencing study of testicular cancer reported to date, our findings do not support the existence of a major high-penetrance TGCT susceptibility gene (of odds ratio >10 and allele frequency [combined]>0.01%). Owing to its power, this study cannot exclude the existence of susceptibility genes responsible for occasional TGCT families or of rare mutations that confer very modest relative risks. In concert with findings from genome-wide association studies, our data support the notion that inherited susceptibility is largely polygenic with substantial contribution from common variation.
In the largest study of its kind, we sequenced ∼20 000 genes in 919 men with testicular germ cell tumour (TGCT) and 1609 TGCT-free individuals and found no evidence of a single major gene underlying predisposition to TGCT (in the manner of BRCA1 for breast cancer). Instead, familial risk of TGCT is likely to be due to varying dosages of hundreds of minor genetic factors.
European urology. 2018 Feb 09 [Epub]
Kevin Litchfield, Chey Loveday, Max Levy, Darshna Dudakia, Elizabeth Rapley, Jeremie Nsengimana, D Tim Bishop, Alison Reid, Robert Huddart, Peter Broderick, Richard S Houlston, Clare Turnbull
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK., Section of Epidemiology & Biostatistics, Leeds Institute of Cancer and Pathology, Leeds, UK., Academic Uro-oncology Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK., Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Division of Molecular Pathology, The Institute of Cancer Research, London, UK., 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; National Cancer Registration and Analysis Service, Public Health England, London, UK. Electronic address: .