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

Nature Reviews Urology volume 13, pages 409–419 (2016)Cite this article

Subjects

Key Points

  • Testicular germ cell tumour (TGCT) has notably high heritability with commensurate high familial relative risks compared with other cancers

  • Genome-wide association studies have identified 25 loci for TGCT, consistent with a highly polygenic architecture underlying the genetic susceptibility

  • Intratubular germ cell neoplasia unclassified, the noninvasive precursor of TGCT, is molecularly similar to primordial germ cells and likely arises during fetal development, lying dormant in the gonads until puberty

  • Testicular tumours are mutationally stable and are characterized by KIT and KRAS mutations at modest frequency. Large-scale chromosomal gains are common in testicular tumours. Nearly all tumours carry isochromosome 12p, which is likely to be a key triggering event for malignant transformation

  • Platinum resistance affects <10% of patients but results in poor outcomes; although extensively investigated through somatic and germline pharmacogenomic studies, the mechanism remains obscure

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.

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Figure 1: The genomic features of testicular germ cell tumours, summarized using a timeline approach.
Figure 2: KIT–KITLG signalling showing genes related to this pathway.
Figure 3: Testicular germ cell tumour susceptibility loci that have been identified through genome-wide association studies.

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Authors and Affiliations

  1. Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK

    Kevin Litchfield, Max Levy & Clare Turnbull

  2. Academic Radiotherapy Unit, Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK

    Robert A. Huddart

  3. Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK

    Janet Shipley

  4. William Harvey Research Institute, Queen Mary University, Charterhouse Square, London, EC1M 6BQ, UK

    Clare Turnbull

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  1. Kevin Litchfield
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  2. Max Levy
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  4. Janet Shipley
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Contributions

K.L. and M.L. researched data for the article, R.A.H., J.S. and C.T. contributed to discussion of its contents. K.L. wrote the manuscript and K.L., M.L. and C.T. reviewed and edited the manuscript before submission.

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Correspondence to Clare Turnbull.

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Litchfield, K., Levy, M., Huddart, R. et al. The genomic landscape of testicular germ cell tumours: from susceptibility to treatment. Nat Rev Urol 13, 409–419 (2016). https://doi.org/10.1038/nrurol.2016.107

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