title: Presence of somatic mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in cisplatin-resistant germ cell tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Authors' Affiliations: Genitourinary Oncology Service, Department of Medicine; Department of Medicine, Weill Medical College of Cornell University; and feldmand@mskcc.org.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Feldman
authors.affiliation: Authors' Affiliations: Genitourinary Oncology Service, Department of Medicine; Human Oncology and Pathogenesis Program; Departments of Department of Medicine, Weill Medical College of Cornell University; and.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Authors' Affiliations: Genitourinary Oncology Service, Department of Medicine;
authors.forename: Lindsay
authors.initials: L
authors.lastname: Van Alstine
authors.affiliation: Epidemiology and Biostatistics; and.
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.affiliation: Pathology, Memorial Sloan-Kettering Cancer Center;
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.affiliation: Pathology, Memorial Sloan-Kettering Cancer Center;
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.affiliation: Authors' Affiliations: Genitourinary Oncology Service, Department of Medicine; Department of Medicine, Weill Medical College of Cornell University; and.
authors.forename: George J
authors.initials: GJ
authors.lastname: Bosl
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, New York City, New York.
authors.forename: Raju S
authors.initials: RS
authors.lastname: Chaganti
authors.affiliation: Authors' Affiliations: Genitourinary Oncology Service, Department of Medicine; Human Oncology and Pathogenesis Program; Departments of Department of Medicine, Weill Medical College of Cornell University; and.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; C494918:AKT1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002945:Cisplatin