Testicular germ cell tumours: predisposition genes and the male germ cell niche

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.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)).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.TERT and ATF7IP maintain telomere length and are reactivated in a range of tumour types.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.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.This improved understanding of TGCT predisposition and biology will lead to further refinements in the clinical management of this disease.