High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia

Abstract

BACKGROUND: The incidence of human papillomavirus-associated vulval neoplasia is increasing worldwide; yet the associated genetic changes remain poorly understood. METHODS: We have used single-nucleotide polymorphism microarray analysis to perform the first high-resolution investigation of genome-wide allelic imbalance in vulval neoplasia. Our sample series comprised 21 high-grade vulval intraepithelial neoplasia and 6 vulval squamous cell carcinomas, with paired non-lesional samples used to adjust for normal copy number variation. RESULTS: Overall the most common recurrent aberrations were gains at 1p and 20, with the most frequent deletions observed at 2q, 3p and 10. Copy-neutral loss of heterozygosity at 6p was a recurrent event in vulval intraepithelial neoplasia. The pattern of genetic alterations differed from the characteristic changes we previously identified in cutaneous squamous cell carcinomas. Vulval neoplasia samples did not exhibit gain at 5p, a frequent recurrent aberration in a series of cervical tumours analysed elsewhere using an identical protocol. CONCLUSION: This series of 27 vulval samples comprises the largest systematic genome-wide analysis of vulval neoplasia performed to date. Despite shared papillomavirus status and regional proximity, our data suggest that the frequency of certain genetic alterations may differ in vulval and cervical tumours.

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

“…HPV‐positive VIN VSCC frequently showed chromosome 1 gains (discussed below), chromosome 3q gain, chromosome 4 loss and chromosome 20 gain. In agreement with this, 2 previous studies on HPV‐positive VIN lesions demonstrated frequent gains at chromosome 1pq, 3q, 19, and/or 20q . Gains of chromosome 1pq, 3q, and 20q were also common in HPV‐positive anal intraepithelial neoplasia .…”

“…In agreement with this, 2 previous studies on HPV-positive VIN lesions demonstrated frequent gains at chromosome 1pq, 3q, 19, and/or 20q. 15,16 Gains of chromosome 1pq, 3q, and 20q were also common in HPV-positive anal intraepithelial neoplasia. 39 The frequent gains of chromosome 1 and 20 and loss of chromosome 4 mentioned above were rarely present in HPV-positive VSCC.…”

“…However, studies on genetic and epigenetic aberrations in VIN and VSCC are limited. 1,2,[12][13][14][15][16] TP53 mutations are frequently (~30%) detected in HPV-negative VSCC as well as HPV-negative VIN (~21%), suggesting that TP53 mutations might be involved at an early stage. 1 Immunohistochemically HPV-positive VIN shows usually absence of p53 and strong p16 expression.…”

“…Molecular markers reflecting genetic and epigenetic host cell alterations associated with vulvar carcinogenesis are expected to be most promising. However, studies on genetic and epigenetic aberrations in VIN and VSCC are limited . TP53 mutations are frequently (~30%) detected in HPV‐negative VSCC as well as HPV‐negative VIN (~21%), suggesting that TP53 mutations might be involved at an early stage .…”

DNA Copy Number Aberrations, and Human Papillomavirus Status in Penile Carcinoma. Clinico-Pathological Correlations and Potential Driver Genes

“…Differences were also seen in comparison of HPV cohorts in oropharyngeal squamous cell carcinomas [ 18 , 44 ], which highlighted Xp gain and 16q loss more common in HPV-positive cases, and 3p, 5q, 9p, 15q and 18q loss more common in HPV-negative cases [ 18 ]. In contrast to these studies, a higher frequency of 1q gain in our HPV-positive cohort is in accordance with HPV-positive VSCCs [ 45 ] and CSCCs [ 46 – 48 ]. Further analysis by Jung et al .…”