azd2014 and Papillomavirus-Infections

Vulvar squamous cell carcinoma (VSCC) constitutes over 90% of vulvar cancer. Its pathogenesis can follow two different pathways; high risk human papillomavirus (hrHPV)-dependent and HPV-independent. Due to the rarity of VSCC, molecular mechanisms underlying VSCC development remain largely unknown. The study aimed to identify pathogenic mutations implicated in the two pathways of VSCC development.. Using next generation sequencing, 81 VSCC tumors, 52 hrHPV(+) and 29 hrHPV(-), were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific).. Mutations of TP53 (46% and 41%, of hrHPV(+) and hrHPV(-) cases respectively) and CDKN2A (p16) (25% and 21%, of hrHPV(+) and hrHPV(-) cases respectively) were the most common genetic alterations identified in VSCC tumors. Further mutations were identified in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, FLT3, JAK3, GNAQ, and PTEN, albeit at low frequencies. Some of the identified mutations may activate the PI3K/AKT/mTOR pathway. The activation of mTOR was confirmed in the vast majority of VSCC samples by immunohistochemical staining.. Detecting pathogenic mutations in 13/50 genes examined at comparable frequencies in hrHPV(+) and hrHPV(-) tumors suggest that genetic mechanisms of the two routes of VSCC pathogenesis may be similar, despite being initiated from different premalignant lesions. Importantly, our data provide a rationale for new anti-VSCC therapies targeting the PI3K/AKT/mTOR pathway.

Topics: Adult; Aged; Aged, 80 and over; AMP-Activated Protein Kinase Kinases; Antibiotics, Antineoplastic; Antineoplastic Agents; Benzamides; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Class I Phosphatidylinositol 3-Kinases; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18; Disease-Free Survival; DNA Mutational Analysis; DNA, Neoplasm; Everolimus; F-Box-WD Repeat-Containing Protein 7; Female; fms-Like Tyrosine Kinase 3; GTP-Binding Protein alpha Subunits, Gq-G11; High-Throughput Nucleotide Sequencing; Humans; Janus Kinase 3; Middle Aged; Morpholines; Mutation; Papillomaviridae; Papillomavirus Infections; Phosphatidylinositol 3-Kinase; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Sirolimus; Smad4 Protein; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53; Vulvar Neoplasms