Simple Epigenetic Test Could Identify Anal Cancer

Liam Davenport

May 31, 2017

A simple and novel test based on an individual's epigenetics could offer a highly accurate and inexpensive way of detecting anal cancer, thus reducing the need for painful procedures to confirm the diagnosis, say British researchers.

The incidence of anal cancer has grown in recent years both in women and among men who have sex with men, with most cases associated with human papillomavirus type 16 (HPV16).

Although high-resolution anoscopy (HRA) is commonly used in primary care to screen high-risk individuals for the disease, it is associated with high costs and subjective results and causes discomfort to the patient.

The new study, published online in the journal Oncotarget on May 18, showed that measuring the degree of DNA methylation associated with HPV16 and a previously identified tumor suppressor gene in anal biopsy specimens could identify anal cancer with a sensitivity of 90%.

Lead researcher, Attila Lorincz, PhD, professor of molecular epidemiology at the Wolfson Institute of Preventive Medicine, Queen Mary University of London, United Kingdom, said in a release that he and his colleagues were "surprised" that just two biomarker genes would yield "such an accurate prediction" of anal cancer.

This means that the cost of any resulting tests, which would likely be based on less invasive swab samples rather than biopsies, will be "fairly low."

Dr Lorincz therefore hopes to see "a big improvement" in care for high-risk individuals "by making sure that anoscopies and laser or chemical surgery are only given to those who need it."

Building on Cervical Cancer Findings

Rachel Orritt, health information at the charity Cancer Research UK, which funded the study, commented: "This study builds on what we already know about the link between changes to cell DNA and cervical cancer, and shows that similar changes to the DNA in anal cells could suggest anal cancer."

"If other studies confirm and build upon these findings, this promising research could be used to develop a less invasive method to help doctors identify people who are at a higher risk of anal cancer and avoid unnecessary procedures for those who are at a lower risk," she added.

Because DNA methylation testing of HPV and human genes has been shown to be an accurate technique for detecting high-grade cervical intraepithelial neoplasia, the researchers examined methylation patterns for HPV and the tumor suppressor gene EPB41L3 in 148 anal and perianal formalin-fixed, paraffin-embedded biopsy specimens.

This included 30 anal biopsy specimens without anal intraepithelial neoplasia (AIN), 43 with low-grade AIN, 59 with high-grade AIN, and 5 with anal cancer, alongside 11 perianal specimens with high-grade AIN.

The team found that 53.3% of anal biopsy specimens without AIN were infected with HPV16, compared with 32.6% of low-grade AIN specimens, 83.0% of high-grade AIN specimens, and 80.0% of cancer specimens. In addition, 90.9% of high-grade AIN perianal biopsy specimens were infected with HPV16.

Approximately one third (47 of 148) of biopsy specimens were infected with multiple HPV types.

Anal biopsy specimens without AIN and those with low-grade AIN were substantially more likely to be infected with low-risk HPV types or be negative for the virus than other biopsy specimen types, at 33.% and 32.6%, respectively, vs 8.5% for high-grade AIN and 0.0% for both anal cancer and high-grade AIN perianal biopsy specimens.

The researchers used a bivariate model to derive a linearly combined DNA methylation score, calculated as 0.561*HPV16 methylation+0.439*EPB41L3. This yielded significantly increasing scores with increasing disease severity, at 8.1% for biopsy specimens without AIN, 13.2% for low-grade AIN specimens, 22.3% for high-grade AIN specimens, and 49.3% for anal cancer specimens (P < .0001).

A cutoff of 8.8 for the DNA methylation score resulted in a sensitivity for detecting high-grade AIN and anal cancer biopsy specimens over benign and low-grade AIN specimens of 90.6%, alongside a specificity of 50.7% and an area under the curve of 0.82.

The team says that their results "need to be replicated in an adequately powered study of exfoliated anal cells because, in routine practice, high-risk HPV-positive patients would have methylation tests performed on exfoliated cells collected by a swab or similar device."

This, they add, would "allow efficient triage to HRA, thus reducing costs, anxiety and possible over-treatment of low-risk people."

Moreover, Dr Lorincz believes that using swabs samples would achieve just as accurate results as those with biopsy specimens and consequently is "the way forward."

He told Medscape Medical News: "We are also doing similar studies in cervical cancer, and there's a very good correlation between the swab samples and the biopsies there."

"Many think the swab samples are even better because they are more representative of what's going on, as you're collecting cells from a much larger area."

He added: "It helps clinicians recognize when they need to look for hidden lesions that they may not have seen, and order a biopsy and so forth."

Dr Lorincz explained that the only reasons why the authors did not use swab samples in the current study is that the clinicians had not collected them, "but we are discussing another study at the moment that's going to be larger than this one, and is going to use swab samples."

He added: "What we also need is for some labs who are routine testing labs to take this on board and, eventually, for companies to make these available as kits," although he noted that this will be in the longer term because it can "take a few years" to reach that stage.

The study was funded by Cancer Research UK. The authors have disclosed no relevant financial relationships.

Oncotarget. Published online May 18, 2017.  Abstract

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