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Epigenetic Score Gauges Risk of Developing Anal Cancer

NEW YORK (GenomeWeb) – Epigenetic changes can distinguish people who may be at high risk of developing anal cancer, a new study has found.

Anal cancer, which is largely caused by the human papillomavirus, is becoming more common among women, men who have sex with men, and people with HIV. According to the US National Cancer Institute, there are some 1.8 new cases of anal cancer per 100,000 people every year, with 0.2 deaths per 100,000 people each year.

As methylation levels have been found to rise in HPV-infected women and are highest in those with cancer, researchers from Queen Mary University of London postulated that epigenetics changes might also occur in anal cancer. As they reported in Oncotarget, they found that epigenetic changes at two sites could portend whether a lesion would progress to cancer and could be used as a test to gauge risk.

"We thought this would require a complicated genomic signature involving hundreds of genes, so we were surprised that we could get such an accurate prediction from just two biomarker genes," QMUL's Attila Lorincz said in a statement. "That's important because the expected cost of the test will be fairly low."

Lorincz and his colleagues collected anal and perianal biopsy samples from 148 patients, 116 of whom were men, 31 of whom were women, and one of whom had no gender recorded. Ninety-four patients were HIV positive. Additionally, 30 of the samples were benign, 43 were low-grade anal intraepithelial neoplasms, 59 were high-grade anal intraepithelial neoplasms, and five were cancer.

By genotyping, the researchers found that a third of samples were infected with multiple types of HPV, with the most common strain being HPV16, which is considered a high-risk strain. According to the researchers, HPV16 was present in more than half the benign biopsies, about a third of the low-grade, and 82 percent of the high-grade lesions. It was also present in four of the five cancerous samples.

Using bisulfite sequencing, the researchers examined methylation levels at the human tumor suppressor gene EPB41L3 and the viral late genomic regions of HPV16, HPV18, HPV31, and HPV33 in each sample. For each marker, they generated a methylation score based on the average of all CpG positions.

Lorincz and his colleagues reported that the DNA methylation levels of EPB41L3, HPV16L1, and HPV16L2 varied significantly between the groups of lesions and that methylation increased with lesion severity.

They developed a bivariate methylation score based on these markers that they combined linearly. The score included three CpG sites in EPB41L3 along with the two late regions of HPV16.

For all three variables — EPB41L3 methylation, HPV16 methylation, and the DNA methylation score — the researchers noted that there was a highly significant trend of increased methylation with disease progression.

Using the methylation score as a triage classifier, the researchers also reported that it had a sensitivity of 90.6 percent, specificity of 50.7 percent, and area under the curve of 0.82 in distinguishing high-grade anal intraepithelial neoplasms and cancer from benign and low-grade anal intraepithelial neoplasms.

This suggested to Lorincz and his colleagues that DNA methylation could be a biomarker of anal disease and may be able to distinguish lesions that will progress from ones that won't. "Now that we can identify those at risk, and conversely, those not at risk, we hope to see a big improvement, by making sure that anoscopies and laser or chemical surgery are only given to those who need it," Lorincz said.

He added that further studies in larger cohorts and with swab, rather than biopsy, samples are needed before a test could be developed.