Somatic Mutation Profiling in Premalignant Lesions of Vulvar Squamous Cell Carcinoma.

Sebastian Zięba,Joanne A De Hullu,Natalia Rusetska,Janusz Kopczyński,Elwira Bakuła-Zalewska,Magdalena Kowalewska,Johanna M A Pijnenborg,Kamil Zalewski,Anne-Floor W Pouwer,Artur Kowalik

doi:10.3390/ijms21144880

Abstract

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.

Highlights

High-grade squamous intraepithelial lesions (HSIL) and differentiated vulvar intraepithelial neoplasia are the precursors of vulvar squamous cell carcinoma (VSCC), as recognized by the current WHO classification [1]
DNA isolated from the analyzed samples (20 lichen sclerosus (LS), 38 HSIL, 19 differentiated vulvar intraepithelial neoplasia (dVIN) and 10 VSCC tumors) was subjected to generation sequencing using the Ion AmpliSeq Cancer Hotspot Panel v2
DNA isolated from the analyzed samples (20 LS, 38 HSIL, 19 dVIN and 10 VSCC tumors) was suchbajencgteesdwteorenideexnttigfiendeinra1t9ioonutsoefq5u0egnenciensgexuamsiinngedt,hi.ee.,IToPn53A, mCDpKliNS2eAq, CFGaFnRc3e,rPHIKo3tCsAp,oFtBPXaWn7e,l v2

Summary

Introduction

High-grade squamous intraepithelial lesions (HSIL) and differentiated vulvar intraepithelial neoplasia (dVIN) are the precursors of vulvar squamous cell carcinoma (VSCC), as recognized by the current WHO classification [1]. The observed increase in the incidence of vulvar premalignant lesions worldwide [7] may be explained by an increasing exposure to HPV and increasing prevalence of smoking among women [8], and by higher detection rates caused by the physician awareness and more liberal evaluation by the use of vulvar biopsies. The incidence rate of invasive vulvar cancer continues to rise, due to both an increase in HPV and the ageing population [10,11]. WHO classification does not consider LS as a direct VSCC premalignant lesion, as long term studies have shown a very low risk of progression to cancer of up to 3.5% [3,12,13], this risk is much higher compared to women without LS. Some studies link LS with dyskeratosis and/or parakeratosis, hyperplasia and basal cellular atypia with HPV-negative vulvar carcinogenesis [14] with approximately 30–60% of VSCC reported to occur on a background of LS [15,16]

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Discussion

Conclusion