Abstract
BackgroundChanges in host tumor genome DNA methylation patterns are among the molecular alterations associated with HPV-related carcinogenesis. However, there is little known about the epigenetic changes associated specifically with the development of anal squamous cell cancer (SCC). We sought to characterize broad methylation profiles across the spectrum of anal squamous neoplasia.Methodology/Principal FindingsTwenty-nine formalin-fixed paraffin embedded samples from 24 patients were evaluated and included adjacent histologically normal anal mucosa (NM; n = 3), SCC-in situ (SCC-IS; n = 11) and invasive SCC (n = 15). Thirteen women and 11 men with a median age of 44 years (range 26–81) were included in the study. Using the SFP10 LiPA HPV-typing system, HPV was detected in at least one tissue from all patients with 93% (27/29) being positive for high-risk HPV types and 14 (93%) of 15 invasive SCC tissues testing positive for HPV 16. Bisulfite-modified DNA was interrogated for methylation at 1,505 CpG loci representing 807 genes using the Illumina GoldenGate Methylation Array. When comparing the progression from normal anal mucosa and SCC-IS to invasive SCC, 22 CpG loci representing 20 genes demonstrated significant differential methylation (p<0.01). The majority of differentially methylated gene targets occurred at or close to specific chromosomal locations such as previously described HPV methylation “hotspots” and viral integration sites.ConclusionsWe have identified a panel of differentially methlylated CpG loci across the spectrum of HPV-associated squamous neoplasia of the anus. To our knowledge, this is the first reported application of large-scale high throughput methylation analysis for the study of anal neoplasia. Our findings support further investigations into the role of host-genome methylation in HPV-associated anal carcinogenesis with implications towards enhanced diagnosis and screening strategies.
Highlights
Anal squamous cell cancers (SCC) account for 4% of all lower gastrointestinal tract malignancies in the United States with an estimated 6,230 new cases and 780 deaths expected in 2012 [1]
We have identified a panel of differentially methlylated CpG loci across the spectrum of human papillomavirus (HPV)-associated squamous neoplasia of the anus
High-risk HPV types were detected in 93% (27/29) of tissues; 3 patients with SCC-in situ (SCC-IS) were positive for low-risk HPV 6
Summary
Anal squamous cell cancers (SCC) account for 4% of all lower gastrointestinal tract malignancies in the United States with an estimated 6,230 new cases and 780 deaths expected in 2012 [1]. Anal intraepithelial neoplasia (AIN) is the precursor lesion of invasive anal SCC. It is generally thought that high grade AIN (HGAIN) or carcinoma in situ, but not low grade lesions, are at risk of malignant progression to invasive anal SCC. Molecular biomarkers of anal neoplasia have the potential to more accurately risk stratify HGAINs and may improve the low sensitivity of HGAIN diagnosis found with anal PAP smears, reducing the need for costly invasive biopsies [9]. There is little known about the epigenetic changes associated with the development of anal squamous cell cancer (SCC). We sought to characterize broad methylation profiles across the spectrum of anal squamous neoplasia
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