CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma.
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.


CONCLUSION
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.
['Trietsch|Marjolijn D|MD|', 'Spaans|Vivian M|VM|', 'ter Haar|Natalja T|NT|', 'Osse|Elisabeth M|EM|', 'Peters|Alexander A W|AA|', 'Gaarenstroom|Katja N|KN|', 'Fleuren|Gert Jan|GJ|']
D000368:Aged D002294:Carcinoma, Squamous Cell D019941:Cyclin-Dependent Kinase Inhibitor p16 D005260:Female D019942:Genes, p16 D006801:Humans D009154:Mutation D009363:Neoplasm Proteins D016283:Proto-Oncogene Proteins p21(ras) D015996:Survival Rate D014846:Vulvar Neoplasms
HRAS Squamous cell carcinoma Somatic mutation Survival CDKN2A Vulva