Gene expression profiles in HPV‐infected head and neck cancer

Abstract

Epidemiological and laboratory evidence indicate that, in addition to tobacco and alcohol, human papillomaviruses (HPV) play an important aetiological role in a subset of head and neck squamous cell carcinoma (HNSCC). To evaluate the molecular pathogenesis of HPV-infected HNSCC, we compared gene expression patterns between HPV-positive and -negative HNSCC tumours using cDNA microarrays. Tumour tissue was collected from 42 histologically confirmed HNSCC patients from an inner-city area of New York. Total DNA and RNA were extracted and purified from frozen tumour samples and gene expression levels were compared to a universal human reference RNA standard using a 27 323 cDNA microarray chip. HPV detection and genotyping were performed using an MY09/11-PCR system and RT-PCR. HPV was detected in 29% of HNSCC tumours. Most harboured only HPV16 and expressed the HPV16-E6 oncogene. HPV prevalence was highest in pharyngeal tumours (45%). Gene expression patterns that differentiated HPV-positive from negative tumours were compared by supervised classification analysis, and a multiple-gene signature was found to predict HPV16 prevalence in primary HNSCC with a false discovery rate < 0.2. Focusing on never-smokers, we further identified a distinct subset of 123 genes that were specifically dysregulated in HPV16-positive HNSCC. Overexpressed genes in HPV-positive HNSCC tumours included the retinoblastoma-binding protein (p18), replication factor-C gene, and an E2F-dimerization partner transcription factor (TFDP2) that have also been found to be overexpressed in cervical cancer. An additional subset of genes involved in viral defence and immune response, including interleukins and interferon-induced proteins, was found to be down-regulated in HPV-positive tumours, supporting a characteristic and unique transcriptional profile in HPV-induced HNSCC.

SERPINE1 and SMA expression at the invasive front predict extracapsular spread and survival in oral squamous cell carcinoma

“…For example, OSCC has a much greater propensity for spread with poor outcomes compared with OPSCC (Franceschi et al, 1993;Dobrossy, 2005;Timar et al, 2005;Yu et al, 2008). This site specificity is also reflected by the presence of HPV, which is known to have a distinct gene expression profile (Ragin et al, 2006;Slebos et al, 2006;Schlecht et al, 2007;Shaw et al, 2010;van Hooff et al, 2012b). We established the HPV status of the cohort using a gold standard test and identified that the presence of HPV was unlikely to be a confounding variable in our analysis.…”

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

“…However, these technologies have had little impact on standard methods for diagnosis and treatment of HNSCC and many other types of cancer with one or more known mutational or copy number drivers. Despite extensive literature of differential gene expression profiles, mutations and copy number abnormalities in head and neck tumors that could potentially impact future clinical applications, little other than HPV status is done routinely upon diagnosis [7,10,11,13,15,24,32,[35][36][37][38][39][40][41][42][43][44][45][46][47]. A main factor contributing to this lack of progress is that no clear directives or actionable guidelines have been adopted for molecularly profiling HNSCCs.…”

“…Recent reports have shown that HPV testing by PCR alone is not sufficient for diagnosis of OPSCC [11,12]. Numerous gene expression studies have been previously used to categorize HPV-positive versus negative OPSCC, and despite numerous reports of the potential clinical benefit of such testing, none of these signatures have been adopted as a routine diagnostic for OPSCC [13].…”

Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma

“…21 In addition, studies investigating gene expression in HPV-positive and HPV-negative HNSCC show distinct transcriptomic patterns, which might be partly due to viral E6-and E7-mediated alterations in the genome and epigenome. [22][23][24][25] One group of different expressed genes is that of DNA methyltransferases, involved in regulation of DNA methylation. 26,27 Differences in methylation profiles between HPV-positive and HPV-negative OPSCC have been explored in many studies, though most promoter methylation studies have evaluated only a limited number of genes and did not focus on solely the oropharynx.…”