Genetics of testicular cancer: a review

Testicular germ cell tumours (TGCTs) are the most common solid malignant cancer diagnosed in young males and the incidence is increasing. Understanding the genetic basis of this disease will help us to navigate the challenges of early detection, diagnosis, treatment, surveillance, and long-term outcomes for patients.

TGCTs are highly heritable. Current understanding of germline risk includes the identification of one moderate-penetrance predisposition gene, checkpoint kinase 2 ( CHEK2 ), and 78 low-to-moderate-risk single nucleotide polymorphisms identified in genome-wide-associated studies, which account for 44% of familial risk. Biomarker research in TGCTs has been challenging for multiple reasons: oncogenesis is complex, actionable mutations are uncommon, clonal evolution unpredictable and tumours can be histologically and molecularly heterogeneous. Three somatic mutations have thus far been identified by DNA exome sequencing, exclusively in seminomas: KIT, KRAS and NRAS . Several genetic markers appear to be associated with risk of TGCT and treatment resistance. TP53 mutations appear to be associated with platinum resistance. MicroRNA expression may be a useful biomarker of residual disease and relapse in future.

The biology of testicular germ cells tumours is complex, and further research is needed to fully explain the high heritability of these cancers, as well as the molecular signatures which may drive their biological behaviour.