Despite an increasing incidence, vulvar squamous cell cancer (VSCC) is still a rare disease. So far two etiological pathways have been described: A high-risk human papillomavirus (HPV)-dependent route and an HPV–independent pathway often associated with lichen sclerosus. To date, therapeutic strategies in VSCC are not influenced by molecularpathological information and therapeutic options for advanced or recurrent disease are limited.
Whole exome sequencing of DNA isolated from 34 VSCC samples and matched normal tissue for each individual was performed on an Illumina HiSeq4000. Short variant discovery was carried out using BWA and MuTect2. Variants were annotated using ANNOVAR. For the detection structural variants and copy number aberrations, Pindel, ADTEx and FREEC were employed. Presence of HPV integration sites was assessed using Bowtie2.
All pts (median age 60) received surgery with (partial) vulvectomy as primary treatment. In 82% a surgical staging of the groins was performed. FIGO stages were: n = 5 IB, n = 13 II, n = 5 stage III and n = 2 IVA (n = 7 unknown). 10/34 (29.4%) samples were HPV positive (all HPV16). 17.6% pts suffered from recurrence (4 local, 2 groin, 1 pelvic) after a median of 10 months. TP53 mutations were most commonly detected, with 41% (14/34). Additionally, we observed mutations in the following genes, which were affected in at least three samples: MUC3A (7/34), FSIP2 (4/34), AKAP9 (4/34), TDRD15, PKD1L1, FCHO1, RANBP2, FBXW7, VPS13C, MDGA2, SCN9A, VEPH1, ABCA5, KIAA0368, NCAM2, GCC2, MYCBP2, PRPF39, WDR49, ZNF729, UTRN, ANKRD36, GRAMD1c, ADGRV1 in 3/34 samples. Significantly less mutations were detected in pts with a OS > 48 months (p = 0.032). However, there was no significant difference in PFS or OS between HPV positive and negative tumors (p = 0.78 and 0.92). In an univariate analysis there was a significant correlation between HPV negative tumors and TP53 mutations (p < 0.0001). No correlation between pT status, pN status, tumor size or number of mutations and HPV status was detected.
The key mutation in vulvar cancer affects TP53. This first work and progress analysis of whole exome sequencing of VSCC with corresponding normal tissue has the potential to identify further key mutations and therewith new targets for the treatment of VSCC.
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All authors have declared no conflicts of interest.