Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors
Menée à partir d'échantillons tumoraux prélevés sur 70 patients américains atteints d'une tumeur à cellules germinales ayant été traitée par une chimiothérapie à base de cisplatine, puis sur neuf lignées cellulaires, cette étude identifie la présence de mutations dans plusieurs gènes (PIK3CA, AKT, RAS, et FGFR3 mais pas BRAF) en association avec la résistance thérapeutique
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 GCT patients at our center. Patients and 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, 1 HRAS). Conclusions: BRAF mutations are rare in American GCT patients, including those with cisplatin-resistance. However, other potentially targetable mutations occur in over 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 GCT, mutations in AKT1 and PIK3CA were observed exclusively in cisplatin-resistant tumors.