Genomic signatures of HPV-independent vulvar squamous cell carcinoma and its precursor lesions

ABSTRACT

Early diagnosis of vulvar squamous cell carcinoma (VSCC) and its precursors is still a challenge to overcome. So far, research on the genomic characterization of VSCC tumors has been limited. We retrospectively analyzed mutational data, histology, and clinical features of eight samples from six patients (including four HPV‐negative VSCC patients with adjacent differentiated vulvar intraepithelial neoplasia (dVIN) tissues, one vulvar lichen sclerosus patient, and one vulvar acanthosis with altered differentiation-like patient). Targeted deep sequencing was performed on these samples with adjacent normal tissues as controls. Only one VSCC patient had moderately/poorly differentiated carcinoma, and neither TP53 nor PIK3CA mutations were identified in this case. Among the remaining seven samples, TERT (7/7) was the most frequently mutated gene, followed by TP53 ( 4/7), CASP8 ( 4/7), and NOTCH1 ( 4/7). Promoter mutation (C228T) was the only alteration seen in the TERT gene. In two patients with paired samples (dVIN + VSCC), one patient showed new single nucleotide variant (SNV) mutation clones, while the other maintained most of the previous SNV mutation clones with acquisition of de novo copy number variations. Further analysis of the entire sample suggested that TP53 (MAP kinase signaling pathway) and CASP8 (apoptosis signaling pathway) are driver genes. Our results indicate that TERT alterations may be the initiating molecular event of VSCC and its precursors as one of several different evolution patterns in the progression of dVIN to VSCC. Moreover, detecting gene mutations such as TERT and CASP8 can be used for the differential diagnosis of VSCC and its precursor lesions.