Methylation of HPV and a tumor suppressor gene reveals anal cancer and precursor lesions.

Attila T Lorincz,Peter Sasieni,Caroline Reuter,Amar Ahmad,Jack Cuzick,Natasa Vasiljevic,Mayura Nathan,Rhian Warman,Michael Sheaff,Mohamed A Thaha

doi:10.18632/oncotarget.17984

Abstract

We studied DNA methylation patterns of human papillomavirus (HPV) and tumor suppressor gene EPB41L3 in 148 anal and perianal biopsies to determine whether high levels of methylation would be associated with anal intraepithelial neoplasia (AIN). The most prevalent HPV type was HPV16, detected in 54% of the 30 benign biopsies, 33% of the 43 low-grade AIN (lgAIN), 82% of the 59 high grade AIN (hgAIN) and 4 of the 5 anal cancers. A methylation score was developed (0.561*HPV16me+0.439*EPB41L3) which had increasing values with severity of disease: the mean was 8.1% in benign, 13.2% in lgAIN, 22.3% in hgAIN and 49.3% in cancers (p < 0.0001). The methylation score as a triage classifier at a cut-off of 8.8 gave a sensitivity of 90.6% (95% CI: 82.8, 96.9), specificity of 50.7% (95% CI: 39.7, 61.6) and area under the curve of 0.82 (95% CI: 0.75–0.89) for separating hgAIN and cancer from benign and lgAIN biopsies. We conclude that methylation of HPV16 and EPB41L3 show highly significant association with increasing severity of AIN and cancer and may be useful as biomarkers in anal disease.

Highlights

Human papillomavirus (HPV) infects a majority of people worldwide
About a third (47/148) of samples were infected with multiple human papillomavirus (HPV) types. 33% of anal biopsies with either
A small proportion (9%) of anal and perianal hgAIN were infected with hrHPV types other than HPV16, i.e. 5 out of 59 of anal and 1 out of 11 of perianal biopsies

Summary

Introduction

Infection can occur at any age and can either be transient (usually resolving within a few years) or could be persistent and last for many decades [1]. High risk HPV (hrHPV) infection with types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 in epithelial basal cells, especially in certain sites such as the uterine cervix, vulva, vagina, anus, and tonsils is an important risk factor for the development of squamous cell cancers and adenocarcinomas [1, 2]. Persistence of hrHPV is a known strong risk factor for cervical cancer [4] and occurs in immunocompetent individuals but is more common in immunosuppressed patients, such as those infected by HIV [5]. Recent widespread www.impactjournals.com/oncotarget recognition that hrHPV testing is much more sensitive than cytology has driven implementation of primary hrHPV screening for cervical disease in many countries [8]

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Conclusion