Molecular heterogeneity in human papillomavirus‐dependent and ‐independent vulvar carcinogenesis

Abstract

Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)‐dependent and ‐independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV‐status and CNA by means of whole‐genome next‐generation shallow‐sequencing were assessed in VSCC and VIN. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during follow‐up (VIN no VSCC). HPV‐testing resulted in 41 HPV‐positive (16 VINVSCC, 14 VIN no VSCC, and 11 VSCC) and 24 HPV‐negative (11 VINVSCC and 13 VSCC) lesions. HPV‐positive and ‐negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV‐negative lesions. HPV‐negative VINVSCC had less CNA than HPV‐negative VSCC (P = .009), but shared chromosome 8 alterations. HPV‐positive VIN no VSCC had less CNA than VINVSCC (P = .022). Interestingly, 1pq gain was detected in 81% of HPV‐positive VINVSCC and only in 21% of VIN no VSCC (P = .001). In conclusion, HPV‐dependent and ‐independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Cancer risk in VIN seems to be reflected by the extent of CNA, in particular chromosome 1 gain in HPV‐positive cases.

Vulvar intraepithelial neoplasia: Incidence and long‐term risk of vulvar squamous cell carcinoma

“…Hence, patients with HSIL could benefit from risk stratification to reduce overtreatment. Molecular biomarkers that could identify dVIN at an early stage and that could cancer risk stratify HSIL are therefore highly needed 45,46 …”

“…Molecular biomarkers that could identify dVIN at an early stage and that could cancer risk stratify HSIL are therefore highly needed. 45,46 ACKNOWLEDGMENT The Dutch Cancer Society has funded this project (Grant number:…”

Genes, pathways and vulvar carcinoma - New insights from next-generation sequencing studies

“…Thus, VSCC can be stratified by HPV status into two distinct diseases not only based on their molecular characteristics but also on patients' prognosis [39], the future improved treatment options are expected to differ for the two disease subtypes [3,5]. However, there are also numerous molecular similarities between the two VSCC subtypes, such as chromosomal abnormalities reported by Swarts et al [40]. Correspondingly, the analyses of somatic genomic alterations of HPV-negative and HPV-positive tumors at other locations (such as head and neck squamous cell carcinoma which shares many similarities with VSCC) reveal many similarities between HPV-related cancers and their HPV-negative counterparts [41].…”

Clinical and molecular classification of vulvar squamous pre-cancers

“…Swarts and colleagues compared copy number alterations in HPV-dependent and HPV-independent VIN using shallow whole-genome sequencing 43. Although there were similarities in some copy number alterations between the HPV positive and HPV negative lesions, particularly gains of 3q and 8q, amplification of 11q/13.3 was exclusively seen in HPV-negative VIN, whereas gains in 1pq were significantly more common in HIV-dependent VIN.…”