We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers.<b>Experimental Design:</b> We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort).
Overexpression of TP53 in precursor lesions (differentiated VIN) and associated invasive carcinomas is regarded as an important diagnostic feature of this subtype of vulvar cancer.
Seventy-four percent of vulvar carcinoma had chromosome 17p-linked loss of heterozygosity, whereas 47% of adjacent lichen sclerosus featured loss of heterozygosity, but only 31% of vulvar carcinoma had p53 mutations, a frequency less than reported previously.
In light of recent studies demonstrating that mutation of p53 gene was found in over 20% of the patients with vulvar carcinoma, a disease of elderly women and a known human papillomavirus (HPV)-related malignancy, we analysed mutation of the p53 gene in 46 women with cervical carcinomas at the age of 60 or more (mean; 71 years, range; 60-96 years).
This study compared the HPV genotype prevalence, HPV-16 variant distribution and p16(INK4a)expression in stored vulvar cancer and high-grade VIN biopsy specimens from women residing in Arnhem Land, with specimens taken from Indigenous and non-Indigenous women in other regions of NT where there is no observed increase in vulvar cancer incidence.
We conclude (1) that p16(INK4a) epigenetic inactivation most likely represents an early event, insufficient for malignant transformation, that may occur in clinically benign lesions such as LS; (2) that lack of pRb was only detected in fewer than one quarter of the carcinomas and could be considered a late secondary event; and (3) that cyclin-D1, which was overexpressed in VC and VIN, could contribute to the malignant transformation in association with p16 hypermethylation.
Univariate and multivariate analyses using stepwise selection were used to identify correlates of abnormal cytology after treatment for VIN and vulvar cancer.
Changes in claudin 1 and claudin 3 expression during progression from VIN to vulvar carcinoma suggests a connection with claudin expression and differentiation of vulvar squamous cells.
Overexpression of TP53 in precursor lesions (differentiated VIN) and associated invasive carcinomas is regarded as an important diagnostic feature of this subtype of vulvar cancer.