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. 2020 Mar-Apr;17(2):151-160.
doi: 10.21873/cgp.20175.

Clonal Relationship Between Lichen Sclerosus, Differentiated Vulvar Intra-epithelial Neoplasia and Non HPV-related Vulvar Squamous Cell Carcinoma

Anne-Floor W Pouwer  1 , Loes C G VAN DEN Einden  2 , Michelle VAN DER Linden  2 , Jayne Y Hehir-Kwa  3   4 , Jiangyan Yu  4 , Koen M Hendriks  3 , Eveline J Kamping  3 , Astrid Eijkelenboom  5 , Leon F A G Massuger  2 , Johan Bulten  5 , Angela A G VAN Tilborg  5 , Joanne A DE Hullu  2 , Roland P Kuiper  3   4
Affiliations

Clonal Relationship Between Lichen Sclerosus, Differentiated Vulvar Intra-epithelial Neoplasia and Non HPV-related Vulvar Squamous Cell Carcinoma

Anne-Floor W Pouwer et al. Cancer Genomics Proteomics. 2020 Mar-Apr.

Abstract

Background/aim: Differentiated vulvar intraepithelial neoplasia (dVIN) and lichen sclerosus (LS) can give rise to vulvar squamous cell carcinoma (VSCC), but genetic evidence is currently still limited. We aimed to determine genetic abnormalities in VSCC and backtrack these abnormalities in the dVIN and LS lesions.

Materials and methods: DNA from VSCC and patient-matched dVIN and LS samples of twelve patients was collected. High-resolution genome-wide copy number analysis was performed and subsequently, we sequenced TP53.

Results: Copy number alterations were identified in all VSCC samples. One dVIN lesion presented with three copy number alterations that were preserved in the paired VSCC sample. Targeted sequencing of TP53 identified mutations in five VSCCs. All five mutations were traced back in the dVIN (n=5) or the LS (n=1) with frequencies ranging from 3-19%.

Conclusion: Our data provide genetic evidence for a clonal relationship between VSCC and dVIN or LS.

Keywords: Vulvar cancer; clonal evolution; differentiated vulvar intraepithelial neoplasia; lichen sclerosus; squamous cell carcinoma; vulvar lichen sclerosus; vulvar neoplasms.

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Conflict of interest statement

None declared.

Figures

Figure 1
Figure 1. Copy number alteration (CNA) profiles of six vulvar squamous cell carcinoma (VSCC) patients. Gains are indicated by the blue bars, and losses are shown by the red bars. Dark colors represent multi-copy gains and losses.
Figure 2
Figure 2. Histological overview of the epithelium of patient three; the area on the left side shows vulvar squamous cell carcinoma (VSCC), the area on the right side differentiated vulvar intra-epithelial neoplasia (dVIN). Micro-dissection was performed in these areas, there is a distance of 2 mm (normal epithelium) between both areas (original magnification ×50).
Figure 3
Figure 3. Shared and different copy number abnormalities in differentiated VIN (dVIN) and vulvar squamous cell carcinoma (VSCC) of patient three. Shown are the high-level amplification on chromosome 11 (A and B) and the deletion of 12q-ter (C), which is shared between the two samples, and the copy number gains on chromosome 8, which is absent in dVIN (D). Detail of the amplification on chromosome 11 (B) shows that its boundaries are identical between the two samples.
Figure 4
Figure 4. Detection TP53 mutations in two vulvar squamous cell carcinoma (VSCC) samples and backtracking in differentiated vulvar intra-epithelial neoplasia (dVIN) and lichen sclerosus (LS). Top panel shows the TP53 protein with the transactivating domain (TAD) and the DNA-dinding domain (DBD) and the location of the two mutations. Below that are sequence chromatograms of each mutation in the respective samples. Mutations are indicated by a black (clonal) or red (subclonal) asteriks.
See this image and copyright information in PMC

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