Abstract
Vulvar squamous cell carcinoma (VSCC) is a rare disease that has a high mortality rate (∼40%). However, little is known about its molecular signature. Therefore, an integrated genomics approach, based on comparative genome hybridization (aCGH) and genome-wide expression (GWE) array, was performed to identify driver genes in VSCC. To achieve that, DNA and RNA were extracted from frozen VSCC clinical specimens and examined by aCGH and GWE array, respectively. On the basis of the integration of data using the CONEXIC algorithm, PLXDC2 and GNB3 were validated by RT-qPCR. The expression of these genes was then analyzed by IHC in a large set of formalin-fixed paraffin-embedded specimens. These analyses identified 47 putative drivers, 46 of which were characterized by copy number gains that were concomitant with overexpression and one with a copy number loss and downregulation. Two of these genes, PLXDC2 and GNB3, were selected for further validation: PLXDC2 was downregulated and GNB3 was overexpressed compared with non-neoplastic tissue. By IHC, both proteins were ubiquitously expressed throughout vulvar tissue. High expression of GNB3 and low PLXDC2 immunostaining in the same sample was significantly associated with less lymph node metastasis and greater disease-free survival. On the basis of a robust methodology never used before for VSCC evaluation, two novel prognostic markers in vulvar cancer are identified: one with favorable prognosis (GNB3) and the other with unfavorable prognosis (PLXDC2). This genomics study reveals markers that associate with prognosis and may provide guidance for better treatment in vulvar cancer. Mol Cancer Res; 14(8); 720-9. ©2016 AACR.
Highlights
Vulvar squamous cell carcinoma (VSCC) is an uncommon disease, constituting 3% to 5% of all malignancies in the female genital tract [1, 2]
We examined a carefully selected subset of VSCC by integrating aCGH and genome-wide expression (GWE) data using validated statistical methods to improve our understanding of vulvar cancer
Sample characterization Eighteen VSCC samples were examined by aCGH analysis, 66.7% of which were classified as VSCC grade 1 or 2 and 72.2% of which had FIGO stage I or II
Summary
Vulvar squamous cell carcinoma (VSCC) is an uncommon disease, constituting 3% to 5% of all malignancies in the female genital tract [1, 2]. VSCC develops primarily in elderly women, after their 70s; the number of cases in younger patients has been climbing, likely due to human papillomavirus (HPV) infection [2]. Despite efforts in the last decade to identify the molecular signature of vulvar cancer, few tumor markers have demonstrated clinical value. Most studies have suggested tumor markers for characterization and VSCC prognostication [3,4,5,6,7]. TP53 mutation and CDKN2A promoter methylation have been associated with VSCC [8,9,10,11]. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/)
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