Genomic profiling of HPV-independent vulvar cancer

The overall aims of the study include: 

1. To identify and characterize genomic profiles of HPV-independent vulvar cancer  
2. To understand and correlate genomic and transcriptomic profiles with prognostic markers and potential treatment targets 

Although rare, the ‎incidence of vulvar squamous cell carcinoma (vSCC) has continuously increased over the past decade. Two main etiological pathways are widely accepted. ‎Roughly 40% of cases are associated with high-risk human papillomavirus (HPV) and are more common ‎in younger women. The remaining 60% are HPV-independent and can be subclassified into 2 groups. The first is typically present in older women, independent of HPV, ‎initiated by TP53 mutation and is often related to chronic skin conditions such as lichen sclerosus. The second HPV-independent subgroup that has been recently ‎reported lacks TP53 mutation and is not well understood. Recent data suggests that these three subtypes of vSCC have distinct clinico-pathologic characteristics and prognostic outcomes.  

Nonetheless, primary treatment is not personalized to the different subgroups and management options are limited for ‎patients with non-resectable or recurrent vSCC with distant metastases. Treatment options, such as ‎antiangiogenic therapy and immune checkpoint inhibition, extrapolated from other cancer types are ‎offered. Genomic characterization has advanced our ‎understanding and treatment options in other cancer types to identify targetable mutations; however, few studies have focused on profiling these HPV-independent vulvar cancers. ‎Comprehensive molecular characterization is thus essential for identifying potential treatment targets and ‎improving long-term strategies in this disease.‎ 

Several research groups have explored the genetic changes in vSCC using next-generation sequencing ‎‎(NGS) panel analysis and whole exome sequencing (WES). Methodological differences, limited sample ‎size and variable HPV detection rates make direct comparisons challenging. Alterations in the pro-oncogenic ‎PI3K/AKT/mTOR pathway, such as mutations in genes like HRAS, KRAS, PIK3CA, KMT2D, and PTEN, ‎have been consistently observed. Specifically, Williams et al. showed that, ‎among 177 patients with HPV-independent vSCC, the most frequent alterations were in TP53, ‎TERTp, CDKN2A, CCND1, and EGFR as well as biomarkers associated with responsiveness to ‎immunotherapy. A 2021 study on 20 vSCC patients compared genomic and transcriptomic data  of 15 HPV-independent to 5 ‎HPV-dependent samples which revealed distinct molecular patterns that significantly correlated with clinical and prognostic factors including overall survival. ‎However, the expression patterns identified by the authors did not overlap with previously reported findings, and ‎this together with the study’s limited sample size hampers generalization of their conclusions. ‎ 

The goal of the present study is to correlate clinical outcomes with genomic, transcriptomic data and clinico-pathologic characteristics in HPV-‎independent vSCC cohort in order to identify dysregulated pathways, prognostic markers, and ‎potential treatment targets‎.