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. 2016 Nov 20;34(33):4000-4007.
doi: 10.1200/JCO.2016.68.7798. Epub 2016 Sep 30.

Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell Tumors

Aditya Bagrodia  1 , Byron H Lee  1 , William Lee  1 , Eugene K Cha  1 , John P Sfakianos  1 , Gopa Iyer  1 , Eugene J Pietzak  1 , Sizhi Paul Gao  1 , Emily C Zabor  1 , Irina Ostrovnaya  1 , Samuel D Kaffenberger  1 , Aijazuddin Syed  1 , Maria E Arcila  1 , Raju S Chaganti  1 , Ritika Kundra  1 , Jana Eng  1 , Joseph Hreiki  1 , Vladimir Vacic  1 , Kanika Arora  1 , Dayna M Oschwald  1 , Michael F Berger  1 , Dean F Bajorin  1 , Manjit S Bains  1 , Nikolaus Schultz  1 , Victor E Reuter  1 , Joel Sheinfeld  1 , George J Bosl  1 , Hikmat A Al-Ahmadie  1 , David B Solit  1 , Darren R Feldman  1
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Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell Tumors

Aditya Bagrodia et al. J Clin Oncol. .

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.

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Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Differences between cisplatin-sensitive and cisplatin-resistant germ cell tumors (GCTs) in the discovery set. (A) Frequency of nonsynonymous mutations identified on whole-exome sequencing was higher among cisplatin-resistant than cisplatin-sensitive GCTs (36 [range, 8-137] v 14 [range, 7-28]; P = .04). (B) Oncoprint displaying the distribution of alterations in TP53, MDM2, KRAS, and NRAS in patients with cisplatin sensitivity and those with cisplatin resistance, as analyzed by whole-exome sequencing. Each column represents an individual patient or sample. Distribution of 12p gain among the discovery set samples is also shown.
Fig 2.
Fig 2.
Genomic alterations among 180 germ cell tumor (GCT) samples in the combined discovery and validation cohorts. (A) Oncoprint displaying the most frequently altered and other biologically notable mutations. (B) TP53 alterations and combined MDM2/TP53 alterations were more common among resistant GCT samples than sensitive ones. Indel, insertion/deletion.
Fig 3.
Fig 3.
Distribution of gene mutations among 180 germ cell tumor (GCT) samples in the combined cohort. (A) TP53 mutations. (B) KIT mutations. The distribution of KIT mutations in GCT differs from GI stromal tumors. (C) Alignment and number of KRAS and RAC1 mutations at the 12, 34, and 61 positions. Expression of the RAC1 mutations identified in GCT results in increased phosphorylation of PAK1 and ERK. Ig, immunoglobulin.
Fig 3.
Fig 3.
Distribution of gene mutations among 180 germ cell tumor (GCT) samples in the combined cohort. (A) TP53 mutations. (B) KIT mutations. The distribution of KIT mutations in GCT differs from GI stromal tumors. (C) Alignment and number of KRAS and RAC1 mutations at the 12, 34, and 61 positions. Expression of the RAC1 mutations identified in GCT results in increased phosphorylation of PAK1 and ERK. Ig, immunoglobulin.
Fig 4.
Fig 4.
Progression-free survival (PFS) by TP53/MDM2 status (wild type v altered) demonstrated superior PFS for patients with wild-type germ cell tumor.
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References

    1. Feldman DR, Bosl GJ, Sheinfeld J, et al. Medical treatment of advanced testicular cancer. JAMA. 2008;299:672–684. - PubMed
    1. Bosl GJ, Motzer RJ. Testicular germ-cell cancer. N Engl J Med. 1997;337:242–253. - PubMed
    1. Feldman DR, Iyer G, Van Alstine L, et al. Presence of somatic mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in cisplatin-resistant germ cell tumors. Clin Cancer Res. 2014;20:3712–3720. - PubMed
    1. Honecker F, Wermann H, Mayer F, et al. Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors. J Clin Oncol. 2009;27:2129–2136. - PubMed
    1. Cheng DT, Mitchell TN, Zehir A, et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17:251–264. - PMC - PubMed

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