The genomic landscape of testicular germ cell tumours: from susceptibility to treatment.
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.
Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK.
Kevin
K
Litchfield
Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK.
Max
M
Levy
Academic Radiotherapy Unit, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK.
Robert A
RA
Huddart
Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK.
Janet
J
Shipley
Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK.|William Harvey Research Institute, Queen Mary University, Charterhouse Square, London EC1M 6BQ, UK.
Clare
C
Turnbull
D000970:Antineoplastic Agents / Q000627:therapeutic use; D053263:Gene Regulatory Networks / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015996:Survival Rate / Q000639:trends; D013736:Testicular Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D016896:Treatment Outcome
D000970:Antineoplastic Agents