Key Points
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Testicular germ cell tumours (TGCTs) are the most frequent solid cancer in young adult Caucasian men; they have shown an increased incidence over the past four decades and are putatively derived from primordial germ cells (PGCs) or gonocytes.
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Genome-wide association studies (GWAS) have revealed loci that suggest predisposition genes that are central to normal PGC biology (KIT ligand (KITLG; also known as SCF), sprouty 4 (SPRY4), BCL-2-antagonist/killer 1 (BAK1), telomerase reverse transcriptase (TERT), activating transcription factor 7 interacting protein (ATF7IP) and doublesex and mab-3-related transcription factor 1 (DMRT1)).
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KITLG, SPRY4 and BAK1 are involved in KIT signalling, which is crucial to PGC migration and survival and is an important pathway that is frequently activated in TGCTs that occur in older men.
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TERT and ATF7IP maintain telomere length and are reactivated in a range of tumour types.
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DMRT1 is responsible for male sex determination. Experimental loss leads to TGCTs in mouse models and genomic gain and overexpression is seen in the spermatocytic seminoma subtype of TGCTs.
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Spermatocytic seminomas exhibit overexpression and mutations of fibroblast growth factor 3 (FGFR3) and HRAS. These mutations confer a selective advantage to the spermatogonial stem cells within the testes and accrue over time, linking ageing to cancer predisposition and congenital syndromes in the offspring of affected gametes.
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This improved understanding of TGCT predisposition and biology will lead to further refinements in the clinical management of this disease.
Abstract
Testicular germ cell tumours (TGCTs) of adults and adolescents are putatively derived from primordial germ cells or gonocytes. Recently reported genome-wide association studies implicate six gene loci that predispose to TGCT development. Remarkably, the functions of proteins encoded by genes within these regions bridge our understanding between the pathways involved in primordial germ cell physiology, male germ cell development and the molecular pathology of TGCTs. Furthermore, this improved understanding of the mechanisms underlying TGCT development and dissemination has clinical relevance for the management of patients with these tumours.
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Acknowledgements
The authors are grateful for funding from the Bob Champion Cancer Trust and the Medical Research Council (Grant 88238). They also acknowledge NHS funding to the NIHR Biomedical Research Centre. The authors are indebted to A. McIntyre, other members of the research team and R. Huddart for their help and support.
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Glossary
- Genome-wide association studies
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These studies (also known as whole-genome association studies) seek to identify associations between SNPs with specific traits across the entire genome by comparing cases and controls.
- Primordial germ cells
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Cells of the germ line that migrate to the gonadal ridges during embryogenesis. Expression profiling suggests that they are similar physiologically to TGCTs and represent a putative cell of origin.
- Intratubular germ cell neoplasia unclassified
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Precursor lesions for TGCTs.
- Hypospadias
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Developmental abnormality of the male genitalia, in which the urethra opens at a variable point along the underside of the penis.
- Genomic imprinting
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The epigenetic modification of DNA that delineates parental origin. It is established during germ cell development and is responsible for the differential expression of imprinted genes in which monoallelic (either paternal or maternal) expression patterns occur.
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Gilbert, D., Rapley, E. & Shipley, J. Testicular germ cell tumours: predisposition genes and the male germ cell niche. Nat Rev Cancer 11, 278–288 (2011). https://doi.org/10.1038/nrc3021
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DOI: https://doi.org/10.1038/nrc3021
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