Presence of somatic mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in cisplatin-resistant germ cell tumors Journal Article

Authors: Feldman, D. R.; Iyer, G.; Van Alstine, L.; Patil, S.; Al-Ahmadie, H.; Reuter, V. E.; Bosl, G. J.; Chaganti, R. S.; Solit, D. B.
Article Title: Presence of somatic mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in cisplatin-resistant germ cell tumors
Abstract: Purpose: A previous study noted frequent B-RAF mutations among European patients with cisplatin-resistant but not cisplatin-sensitive germ cell tumors (GCT). We sought to validate this finding by assessing for these mutations among patients with GCT at our center. Experimental Design: Adolescent and adult patients with GCT who received cisplatin-based chemotherapy and had tumor tissue available were eligible for participation. Response to cisplatin was reviewed to determine sensitivity and resistance. Tumor DNA was extracted and subjected to Sequenom analysis to detect hotspot alterations in FGFR3 , AKT1, PIK3CA, KRAS, HRAS, NRAS, and BRAF with Sanger sequencing for confirmation. Nine GCT cell lines with varying degrees of cisplatin sensitivity and resistance were also assayed by Sequenom. Results: Seventy (24 cisplatin-sensitive; 46 cisplatin-resistant) of 75 patients had tumors with sufficient quality DNA to perform Sequenom. Nineteen mutations were detected among 16 (23%) patients but no BRAF mutations were identified. Similarly, none of the cell lines harbored BRAF mutations. FGFR3 was the most frequent mutation, identified in 13% of both sensitive and resistant samples. All other mutations were exclusive to resistant cases (3 KRAS, 3 AKT1, 3 PIK3CA, and 1 HRAS). Conclusions: BRAF mutations are rare in American patients with GCT, including those with cisplatin resistance. However, other potentially targetable mutations occur in more than 25% of cisplatin-resistant patients. FGFR3, AKT1, and PIK3CA mutations are all reported for the first time in GCT. Whereas FGFR3 mutations occurred with equal frequency in both sensitive and resistant GCTs, mutations in AKT1 and PIK3CA were observed exclusively in cisplatin-resistant tumors. ©2014 AACR.
Journal Title: Clinical Cancer Research
Volume: 20
Issue: 14
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2014-07-15
Start Page: 3712
End Page: 3720
Language: English
DOI: 10.1158/1078-0432.ccr-13-2868
PROVIDER: scopus
PUBMED: 24812411
Notes: Export Date: 1 August 2014 -- CODEN: CCREF -- Source: Scopus
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MSK Authors
  1. Sujata Patil
    383 Patil
  2. David Solit
    431 Solit
  3. Darren Richard Feldman
    171 Feldman
  4. Gopakumar Vasudeva Iyer
    125 Iyer
  5. Victor Reuter
    900 Reuter
  6. Raju S K Chaganti
    262 Chaganti
  7. George Bosl
    255 Bosl