Epigenetic changes are promising biomarkers for gastric cancer

Last Updated: 2017-01-10

By Lorraine L. Janeczko

NEW YORK (Reuters Health) - Epigenetic changes such as DNA methylation may help predict gastric cancer risk, according to extended follow-up results from a large prospective study in Japan.

"The vast majority of human cancers develop due to accumulation of mutations and aberrant DNA methylation," senior author Dr. Toshikazu Ushijima of the National Cancer Center Research Institute in Tokyo told Reuters Health by email. "These final results based on the five-year follow-up of our study convincingly show that the accumulation of aberrant DNA methylation in 'normal' cells is really associated with cancer development."

In 2014, Dr. Ushijima and his team reported results from a study they had conducted to evaluate the usefulness of an epigenetic risk marker for gastric metachronous cancers (http://bit.ly/2izP0HR).

The researchers enrolled 826 Japanese patients between 40 and 80 years of age with early gastric cancer who planned to undergo or who had already undergone endoscopic submucosal dissection between 2008 and 2010 at one of three medical centers.

They took biopsy samples from the lesser curvature in the antrum 2 cm from the pyloric ring for DNA methylation analysis, and they tested the methylation levels of three genes (miR-124a-3, EMX1 and NKX6-1) by quantitative methylation-specific polymerase chain reaction.

Over a median annual follow-up by endoscopy of nearly three years, 66 patients developed metachronous gastric cancer one year or more from enrollment.

"We were very surprised by the results of the three-year follow-up of cancer patients who already had a high risk of developing additional new cancer even after curative treatment of the original cancer. No other methods could predict the risk of metachronous cancer with certainty, but DNA methylation in 'normal' tissue was able to do that," he added.

The five-year results, published online December 21 in Gut, are based on 795 patients from the original cohort who received annual follow-ups over a median of 5.46 years; 133 patients developed metachronous gastric cancer, 116 of them one year or more after enrollment.

The patients were divided into quartiles according to the methylation levels in each of their three genes. The patients in the highest quartile for each of the three genes had a significantly higher risk of developing metachronous cancer than those in the lowest, a finding that held true after adjustment for multiple variables.

For instance, the adjusted hazard of developing the disease was three times greater in patients with the highest vs. lowest quartile of DNA methylation levels of miR-124a-3 (p=0.0017).

"Some people might have been suspicious about the original three-year results, but very few people will be about the five-year results," Dr. Ushijima said.

Dr. Ajlan Atasoy, assistant professor of oncology at Roswell Park Cancer Institute in Buffalo, New York, told Reuters Health by email, "This five-year follow-up provides us valuable and convincing long-term data on a large number patients, but with very specific characteristics: Japanese patients with early gastric cancer treated with endoscopic resection."

"Further studies in different populations from different parts of the world, and including different etiologies and stages of gastric cancer would need to be added to this important evidence to move epigenetic risk stratification closer to global clinical practice. Nevertheless, epigenetic research remains crucial and these updated results contribute significantly to global efforts in this poor-prognosis disease," said Dr. Atasoy, who was not involved in the study.

"The utility of epigenetics has been rapidly growing in biomedical oncologic research and treatment, from epigenetic drugs used in some types of hematologic cancers, to prognostic and predictive biomarkers in different types of solid tumors," she added.

Dr. Ushijima said his team is halfway through recruiting for a multi-institutional study of 2,000 healthy participants with eradicated H. pylori, which has been associated with high methylation levels in gastric mucosa.

"The new study contains people with almost no risk of developing cancer as well as those with high risk. Therefore, we will be able to identify sub-populations who do not need annual cancer screening and those who do," he said.

The study had no commercial funding, and the researchers declared competing interests.

SOURCE: http://bit.ly/2i8RjVV

Gut 2016.