DNA Methylation Profiling across the Spectrum of HPV-Associated Anal Squamous Neoplasia

Jonathan M. Hernandez, Erin M. Siegel, Bridget Riggs, Steven Eschrich, Abul Elahi, Xiaotao Qu, Abidemi Ajidahun, Anders Berglund, Domenico Coppola, William M. Grady, Anna R. Giuliano, David Shibata

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Abstract

Background: Changes 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 Findings: Twenty-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. Conclusions: We 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.

Original languageEnglish (US)
Article numbere50533
JournalPloS one
Volume7
Issue number11
DOIs
StatePublished - Nov 30 2012

Fingerprint

Squamous Cell Neoplasms
Methylation
DNA Fingerprinting
DNA methylation
DNA Methylation
methylation
neoplasms
Genes
Neoplasms
carcinogenesis
loci
mucosa
Carcinogenesis
Mucous Membrane
Genome
Tissue
Anus Neoplasms
Human papillomavirus 16
Virus Integration
bisulfites

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Hernandez, J. M., Siegel, E. M., Riggs, B., Eschrich, S., Elahi, A., Qu, X., ... Shibata, D. (2012). DNA Methylation Profiling across the Spectrum of HPV-Associated Anal Squamous Neoplasia. PloS one, 7(11), [e50533]. https://doi.org/10.1371/journal.pone.0050533

DNA Methylation Profiling across the Spectrum of HPV-Associated Anal Squamous Neoplasia. / Hernandez, Jonathan M.; Siegel, Erin M.; Riggs, Bridget; Eschrich, Steven; Elahi, Abul; Qu, Xiaotao; Ajidahun, Abidemi; Berglund, Anders; Coppola, Domenico; Grady, William M.; Giuliano, Anna R.; Shibata, David.

In: PloS one, Vol. 7, No. 11, e50533, 30.11.2012.

Research output: Contribution to journalArticle

Hernandez, JM, Siegel, EM, Riggs, B, Eschrich, S, Elahi, A, Qu, X, Ajidahun, A, Berglund, A, Coppola, D, Grady, WM, Giuliano, AR & Shibata, D 2012, 'DNA Methylation Profiling across the Spectrum of HPV-Associated Anal Squamous Neoplasia', PloS one, vol. 7, no. 11, e50533. https://doi.org/10.1371/journal.pone.0050533
Hernandez JM, Siegel EM, Riggs B, Eschrich S, Elahi A, Qu X et al. DNA Methylation Profiling across the Spectrum of HPV-Associated Anal Squamous Neoplasia. PloS one. 2012 Nov 30;7(11). e50533. https://doi.org/10.1371/journal.pone.0050533
Hernandez, Jonathan M. ; Siegel, Erin M. ; Riggs, Bridget ; Eschrich, Steven ; Elahi, Abul ; Qu, Xiaotao ; Ajidahun, Abidemi ; Berglund, Anders ; Coppola, Domenico ; Grady, William M. ; Giuliano, Anna R. ; Shibata, David. / DNA Methylation Profiling across the Spectrum of HPV-Associated Anal Squamous Neoplasia. In: PloS one. 2012 ; Vol. 7, No. 11.
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abstract = "Background: Changes 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 Findings: Twenty-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. Conclusions: We 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.",
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AB - Background: Changes 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 Findings: Twenty-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. Conclusions: We 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.

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