title: CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma.
abstract: BACKGROUND
  Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs).
  
  
  METHODS
  A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry.
  
  
  RESULTS
  Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53=58, CDKN2A(p16)=14, HRAS=10, PIK3CA=7, PPP2R1A=3, KRAS=1, PTEN=1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P=.035), with a large effect from patients carrying HRAS-mutations.
  
  
  CONCLUSIONS
  Somatic mutations were detected in 62% of VSCCs. As expected, HPV infection and TP53-mutations play a key role in the development of VSCC, but CDKN2A(p16), HRAS, and PIK3CA-mutations were also frequently seen in HPV-negative patients. Patients with somatic mutations, especially HRAS-mutations, have a significantly worse prognosis than patients lacking these changes, which could be of importance for the development of targeted therapy.
authors: Department of Pathology, Leiden University Medical Center, The Netherlands. Electronic address: M.D.Trietsch@LUMC.nl.
authors: Marjolijn D
authors: MD
authors: Trietsch
authors: Department of Pathology, Leiden University Medical Center, The Netherlands; Department of Gynecology, Leiden University Medical Center, The Netherlands.
authors: Vivian M
authors: VM
authors: Spaans
authors: Department of Pathology, Leiden University Medical Center, The Netherlands.
authors: Natalja T
authors: NT
authors: ter Haar
authors: Department of Pathology, Leiden University Medical Center, The Netherlands.
authors: Elisabeth M
authors: EM
authors: Osse
authors: Department of Gynecology, Leiden University Medical Center, The Netherlands.
authors: Alexander A W
authors: AA
authors: Peters
authors: Department of Gynecology, Leiden University Medical Center, The Netherlands.
authors: Katja N
authors: KN
authors: Gaarenstroom
authors: Department of Pathology, Leiden University Medical Center, The Netherlands.
authors: Gert Jan
authors: GJ
authors: Fleuren
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D019942:Genes, p16; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015996:Survival Rate; D014846:Vulvar Neoplasms / Q000235:genetics* / Q000401:mortality
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CDKN2A; HRAS; Somatic mutation; Squamous cell carcinoma; Survival; Vulva