Human male germ cell tumor resistance to cisplatin is linked to tp53 gene mutation

ABSTRACT Male germ cell tumors (GCTs) are uniquely sensitive to cisplatin-based chemotherapy, with more than 90% of newly diagnosed cases cured. The underlying cause for resistance to

treatment in 20–30% of metastatic lesions remains to be identified. Unlike other solid tumors, no mutations in the TP53 gene have been identified to date in random panels of GCT specimens,

which could account for the exquisite sensitivity of these tumors to genotoxic insult. However, in a panel of resistant GCTs that did either not respond to cisplatin-based chemotherapy or

subsequently relapsed and resulted in the death of the patient, we have now identified a subset of tumors to contain TP53 mutations within exons 6–9. A cell line derived from one of these

tumors (228A) displayed the same TP53 mutation as the tumor specimen, expressed only mutant TP53 mRNA, and exhibited a relative resistance to cisplatin _IN VITRO_ in comparison to a cell

line (218A) derived from a responsive tumor with wild-type TP53. The resistant cell line displayed a much reduced apoptotic cell death and did not exhibit an induction of transcription of

the p53-responsive genes WAF1 and MDM2 following cisplatin treatment, compared to that observed in the sensitive cell line. The levels of bax, an agonist of apoptosis, were found to be

reduced in the resistant cell line. The simplest explanation for the resistance of this subset of GCTs that are resistant to cisplatin-based chemotherapy, is the inability of the cells to

mount an apoptotic response following exposure due to a functionally inactivating mutation in the TP53 gene. Access through your institution Buy or subscribe This is a preview of

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AUTHOR INFORMATION Author notes * VVVS Murty Present address: Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, 10032, NY, USA AUTHORS AND

AFFILIATIONS * Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, NY, USA Jane Houldsworth, Weiyi Chen, Beevash Ray & RSK Chaganti *

Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, NY, USA Han Xiao & George J Bosl * Department of Human Genetics, Memorial

Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, NY, USA VVVS Murty & RSK Chaganti * Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue,

New York, 10021, NY, USA Victor E Reuter Authors * Jane Houldsworth View author publications You can also search for this author inPubMed Google Scholar * Han Xiao View author publications

You can also search for this author inPubMed Google Scholar * VVVS Murty View author publications You can also search for this author inPubMed Google Scholar * Weiyi Chen View author

publications You can also search for this author inPubMed Google Scholar * Beevash Ray View author publications You can also search for this author inPubMed Google Scholar * Victor E Reuter

View author publications You can also search for this author inPubMed Google Scholar * George J Bosl View author publications You can also search for this author inPubMed Google Scholar *

RSK Chaganti View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Houldsworth, J., Xiao, H., Murty, V. _et al._ Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation. _Oncogene_ 16, 2345–2349 (1998).

https://doi.org/10.1038/sj.onc.1201770 Download citation * Received: 01 August 1997 * Revised: 01 December 1997 * Accepted: 03 December 1997 * Published: 26 May 1998 * Issue Date: 07 May

1998 * DOI: https://doi.org/10.1038/sj.onc.1201770 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link

is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * TP53 * mutation * resistance * germ cell tumor