Marking the way to better cancer treatment
Despite the substantial attention cancer research has received over the past few decades, it remains one of the leading causes of death around the world, accounting for nearly 10 million deaths each year. Undaunted by this statistic, researchers continue to study the causes of cancer, disease progression, detection methods and different treatments. In recent years, scientists have relied more and more on epigenetic biomarkers to treat cancers. As reported in a news item posted on ‘News-Medical.net’, this has led to the increasing availability of diagnostic tests for DNA methylation. However, despite increasing efforts in DNA methylation profiling of cancer patients, there are still not enough epigenetic biomarkers to predict whether a cancer treatment will be successful. Researchers supported by the EU-funded COMBAT-RES project sought to address this deficiency. Their study was published in the journal ‘Communications Biology’.
But first, what is DNA methylation?
The National Human Genome Research Institute defines methylation as “a chemical modification of DNA and other molecules that may be retained as cells divide to make more cells. When found in DNA, methylation can alter gene expression.” Abnormal DNA methylation affects many important cancer formation signalling pathways, including those that cause drug resistance or induce drug toxicity. Identifying a patient’s cancer type can provide valuable information that could make treatments more effective and less toxic. In the COMBAT-RES study, the research team looked for epigenetic biomarkers to predict cancer treatment efficacy. To achieve this, they analysed the methylation patterns of 72 cancer cell lines representing 22 cancer types treated with 453 anti-tumour compounds. The research yielded a total of 802 drug differentially methylated regions (dDMRs) – genomic regions that have different DNA methylation patterns among multiple samples. An estimated 377 of these dDMRs showed at least one significantly associated gene near its genomic region. The ‘News-Medical.net’ news item discusses further: “Certain drugs were found to be enriched within certain types of cancer, as demonstrated by drugs targeting the ERK-MAPK signalling pathway being enriched in colorectal cancer. Whereas drugs targeting epidermal growth factor receptor (EGFR) [were] enriched in lung adenocarcinoma, drugs that targeted mitosis were enriched in small-cell lung cancer.”
Study findings expand the cancer research base
About 500 genes were found near identified dDMRs, 27 of which were cancer genes. The APC and SKI cancer genes were the most prevalent across two cancer types. As for the most prevalent non-cancer genes, PTPRN2 and DKK1 were found in five and four cancer types, respectively. The researchers analysed the expression and drug response of each gene associated with a dDMR. Out of the 241 dDMRs, a total of 58 tumour-generalisable dDMRs (tgdDMRs) were identified and positively correlated with their proximal genes in tumours. An estimated 19 of the 58 tgdDMRs contained proposed biomarkers for 17 anti-cancer drugs across five cancer types, and 15 of these 19 tgdDMRs were found in promoter regions. The rest of the biomarkers – over 20 % of the study’s lead biomarkers – were located in either the gene body or distal regions. “The study findings indicate that tgdDMR methylation may either facilitate the ability of cancer cells to interfere in key cellular signalling pathways or participate in other epigenetic pathways,” the news item states. COMBAT-RES (Predicting potent drug combinations by exploiting monotherapy resistance) ends in December 2025. For more information, please see: COMBAT-RES project
Keywords
COMBAT-RES, cancer, biomarker, epigenetic, DNA methylation, drug, gene, cancer research