The genomic landscape of testicular germ cell tumours: from susceptibility to treatment

Abstract

The genomic landscape of testicular germ cell tumour (TGCT) can be summarized using four overarching hypotheses. Firstly, TGCT risk is dominated by inherited genetic factors, which determine nearly half of all disease risk and are highly polygenic in nature. Secondly KIT-KITLG signalling is currently the major pathway that is implicated in TGCT formation, both as a predisposition risk factor and a somatic driver event. Results from genome-wide association studies have also consistently suggested that other closely related pathways involved in male germ cell development and sex determination are associated with TGCT risk. Thirdly, the method of disease formation is unique, with tumours universally stemming from a noninvasive precursor lesion, probably of fetal origin, which lies dormant through childhood into adolescence and then eventually begins malignant growth in early adulthood. Formation of a 12p isochromosome, a hallmark of TGCT observed in nearly all tumours, is likely to be a key triggering event for malignant transformation. Finally, TGCT have been shown to have a distinctive somatic mutational profile, with a low rate of point mutations contrasted with frequent large-scale chromosomal gains. These four hypotheses by no means constitute a complete model that explains TGCT tumorigenesis, but advances in genomic technologies have enabled considerable progress in describing and understanding the disease. Further advancing our understanding of the genomic basis of TGCT offers a clear opportunity for clinical benefit in terms of preventing invasive cancer arising in young men, decreasing the burden of chemotherapy-related survivorship issues and reducing mortality in the minority of patients who have treatment-refractory disease.

Chemotherapy-Induced Depletion of OCT4-Positive Cancer Stem Cells in a Mouse Model of Malignant Testicular Cancer

“…Similar susceptibility factors have been identified in human TGCTs, including PTEN and KITLG (Litchfield et al, 2016). Inactivating PTEN mutations in humans specifically mark the transition from TGCT precursor lesions to invasive germ cell tumors (Di Vizio et al, 2005).…”

“…Inactivating PTEN mutations in humans specifically mark the transition from TGCT precursor lesions to invasive germ cell tumors (Di Vizio et al, 2005). The most common chromosomal aberration in human TGCTs is isochromosome 12p (Litchfield et al, 2016), an additional copy of a region from the small arm of Chromosome 12 which contains the KRAS oncogene ( KRAS2 ) as well as several stem cell-related genes ( NANOG, STELLA , and others).…”

Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis

“…However, NSGCT is known to be relatively simple tumor with a markedly low rate of somatic mutations (21). In addition, certain malignant tumors do not have any putative driver mutations [19], while benign tumors and normal tissues do [20, 21]. Importantly, available data have demonstrated that such genetic aberrations are likely to be similarly distributed among the different components of a mixed NSGCT [9–12, 22, 23].…”

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

“…An Ala193Asp mutation in KITLG has also been shown to cause piebald coat color phenotypes in cattle breeds (Seitz et al 1999;Qanbari et al 2014). Of note, cis-regulatory KITLG variation may provide tissue-specific effects that limit its potential deleterious pleiotropic effects on cancer risks, as observed in other variant forms of this locus in humans (Karyadi et al 2013;Litchfield et al 2016).…”