Functions of genes related to testicular germ cell tumour development

Abstract

Objective: Testicular germ cell tumour (TGCT) is a malignancy with a high heritable component. The inherited risk is polygenic, and around 50 susceptibility genes are identified. The functional role of the gene products for TGCT development is not well understood. The focus of this review is functional studies of genetic risk factors for TGCT derived from GCNIS and the signalling pathways involved in the pathogenesis. Recent developments: Genome-wide association studies have identified new risk loci for TGCT and confirmed previously identified susceptibility genes. Many of these risk genes are related to male germ cell development, sex determination and genomic integrity. Gain-and loss-of-function studies in animal models and TGCT cell lines, as well as gene and protein expression studies in TGCT patient samples, have contributed to the understanding of TGCT development. KITLG-KIT signalling is of crucial importance, but several other signal transduction pathways may also play a role. Many of the risk loci are in non-coding regions, and studies have revealed that non-coding RNAs may act as oncogenes or tumour suppressors in TGCT development. Conclusions: The risk of TGCT is polygenic, and the underlying molecular mechanisms are complex. Several signalling pathways are related to TGCT development, and both proteins and non-coding RNAs may act as oncogenes or tumour suppressors. Epigenetic studies are of importance to get further knowledge about how the signalling pathways are regulated. Hypermethylation of the 5' CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis. Br J Cancer 92, 760-769. Manuylov NL, Fujiwara Y, Adameyko II, Poulat F & Tevosian SG. (2007) The regulation of Sox9 gene expression by the GATA4/FOG2 transcriptional complex in dominant XX sex reversal mouse models. Dev Biol 307, 356-367.

Serum RNA Profiling in the 10-Years Period Prior to Diagnosis of Testicular Germ Cell Tumor

“…The susceptibility to TGCT is shown to have a strong familial link, with a fourfold increased risk for fathers and eightfold for brothers (4,5). The polygenic nature of TGCT has been recognized and more than 50 susceptibility genes have been identified (6)(7)(8)(9). The susceptibility loci contain genes linked to germ cell development and sex determination, as well as genes related to tumor growth/suppression.…”

“…Small RNA sequencing performed on TGCT tissue samples revealed miRNAs profiles to differ between normal and TGCT tissues, as well as between histological subtypes. A genome wide downregulation or loss of piRNAs was observed in TGCT, through mechanisms such as hypermethylation in CpG islands on genes associated with piRNAs ( 8 , 31 – 33 ).…”

Serum RNA profiling in the 10-year period prior to diagnosis of testicular germ cell tumour

“…The susceptibility to TGCT is shown to have a strong familial link, with a fourfold increased risk for fathers and eightfold for brothers [Hemminki and Li, 2004; Dong et al, 2001]. The polygenic nature of TGCT has been recognised and more than 50 susceptibility genes have been identified [Kristiansen et al, 2015; Wang et al, 2017; Litchfield et al, 2018; Das et al, 2019]. The susceptibility loci contain genes linked to germ cell development and sex determination, as well as genes related to tumour growth/suppression.…”

“…Small RNA sequencing performed on TGCT tissue samples revealed miRNAs profiles to differ between normal and TGCT tissues, as well as between histological subtypes. A genome wide downregulation or loss of piRNAs was observed in TGCT, through mechanisms such as hypermethylation in CpG islands on genes associated with piRNAs [Rounge et al, 2015; Ferreira et al, 2014; Das et al, 2019].…”

Testicular germ cell cancer: recent developments in biology and clinical management

“…Specific oncogenic driver mutations have not been identified in TGCT, and there is a striking paucity of recurrent somatic mutations, except for KIT, KRAS and NRAS mutations, identified mainly in seminomas (Shen et al , ). KIT‐ and RAS signalling and other possible pathways indicated by GWAS to be involved in TGCT pathogenesis have been reviewed in two articles in this issue (Das et al , ; Lafin et al , ).…”