Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors Journal Article

Authors: Bagrodia, A.; Lee, B. H.; Lee, W.; Cha, E. K.; Sfakianos, J. P.; Iyer, G.; Pietzak, E. J.; Gao, S. P.; Zabor, E. C.; Ostrovnaya, I.; Kaffenberger, S. D.; Syed, A.; Arcila, M. E.; Chaganti, R. S.; Kundra, R.; Eng, J.; Hreiki, J.; Vacic, V.; Arora, K.; Oschwald, D. M.; Berger, M. F.; Bajorin, D. F.; Bains, M. S.; Schultz, N.; Reuter, V. E.; Sheinfeld, J.; Bosl, G. J.; Al-Ahmadie, H. A.; Solit, D. B.; Feldman, D. R.
Article Title: Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors
Abstract: Purpose: Owing to its exquisite chemotherapy sensitivity, most patients with metastatic germ cell tumors (GCTs) are cured with cisplatin-based chemotherapy. However, up to 30% of patients with advanced GCT exhibit cisplatin resistance, which requires intensive salvage treatment, and have a 50% risk of cancer-related death. To identify a genetic basis for cisplatin resistance, we performed whole-exome and targeted sequencing of cisplatin-sensitive and cisplatin-resistant GCTs. Methods: Men with GCT who received a cisplatin-containing chemotherapy regimen and had available tumor tissue were eligible to participate in this study. Whole-exome sequencing or targeted exon-capture-based sequencing was performed on 180 tumors. Patients were categorized as cisplatin sensitive or cisplatin resistant by using a combination of postchemotherapy parameters, including serum tumor marker levels, radiology, and pathology at surgical resection of residual disease. Results: TP53 alterations were present exclusively in cisplatin-resistant tumors and were particularly prevalent among primary mediastinal nonseminomas (72%). TP53 pathway alterations including MDM2 amplifications were more common among patients with adverse clinical features, categorized as poor risk according to the International Germ Cell Cancer Collaborative Group (IGCCCG) model. Despite this association, TP53 and MDM2 alterations predicted adverse prognosis independent of the IGCCCG model. Actionable alterations, including novel RAC1 mutations, were detected in 55% of cisplatin-resistant GCTs. Conclusion: In GCT, TP53 and MDM2 alterations were associated with cisplatin resistance and inferior outcomes, independent of the IGCCCG model. The finding of frequent TP53 alterations among mediastinal primary nonseminomas may explain the more frequent chemoresistance observed with this tumor subtype. A substantial portion of cisplatin-resistant GCTs harbor actionable alterations, which might respond to targeted therapies. Genomic profiling of patients with advanced GCT could improve current risk stratification and identify novel therapeutic approaches for patients with cisplatin-resistant disease. © 2016 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 34
Issue: 33
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2016-11-20
Start Page: 4000
End Page: 4007
Language: English
DOI: 10.1200/jco.2016.68.7798
PROVIDER: scopus
PUBMED: 27646943
PMCID: PMC5477828
Notes: Article -- Export Date: 6 December 2016 -- Source: Scopus
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MSK Authors
  1. Dean Bajorin
    382 Bajorin
  2. David Solit
    420 Solit
  3. Darren Richard Feldman
    164 Feldman
  4. Gopakumar Vasudeva Iyer
    121 Iyer
  5. Emily Craig Zabor
    119 Zabor
  6. Joel Sheinfeld
    192 Sheinfeld
  7. Sizhi Gao
    28 Gao
  8. Michael Forman Berger
    373 Berger
  9. Maria Eugenia Arcila
    328 Arcila
  10. Victor Reuter
    890 Reuter
  11. Manjit S Bains
    220 Bains
  12. Raju S K Chaganti
    257 Chaganti
  13. George Bosl
    251 Bosl
  14. Nikolaus D Schultz
    193 Schultz
  15. Jana Eng
    6 Eng
  16. William Lee
    38 Lee
  17. Aijazuddin Syed
    20 Syed
  18. Eugene K. Cha
    56 Cha
  19. Byron Hing Lung Lee
    14 Lee
  20. Eugene J Pietzak
    17 Pietzak
  21. Joseph   Hreiki
    5 Hreiki
  22. Ritika   Kundra
    15 Kundra