Somatic Mutation Profiling in Premalignant Lesions of Vulvar Squamous Cell Carcinoma

Vulvar squamous cell carcinoma (VSCC) originates from the progression of either a high-grade squamous intraepithelial lesion (HSIL) or differentiated-type vulvar intraepithelial neoplasia (dVIN), often in a background of lichen sclerosus (LS). The mechanisms leading to the progression of these premalignant lesions to VSCC are elusive. This study aims to identify pathogenic mutations implicated in VSCC development. Using next-generation sequencing, 38 HSIL, 19 dVIN, 20 LS, of which 10 were solitary lesions and 10 with adjacent VSCC, and 10 VSCC adjacent to LS, were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). Pathogenic mutations of TP53 were the most common genetic alterations identified in 53% and 24% of dVIN and HSIL cases, respectively, followed by CDKN2A (p16) mutated in 42% and 0% of dVIN and HSIL, respectively. Seven (70%) and three (30%) of 10 cases of VSCC associated with LS carried TP53 and CDKN2A mutations, respectively, whereas neither solitary LS nor LS associated with VSCC cases harbored mutations in these genes. It appears that TP53 mutations are early events during VSCC carcinogenesis, being present in both HSIL and dVIN lesions. Our preliminary data do not support a genetic background for the notion of LS as the VSCC premalignant lesion.