Epigenetic analysis of gastric cancer finds new disease subtypes
The first full survey of the DNA methylation landscape in gastric cancer
- Date : 19 Oct 2012
- Topic : Gastrointestinal cancers
Researchers at the Duke-NUS Graduate Medical School in Singapore have identified numerous new subtypes of gastric cancer that are triggered by environmental factors. Reported in the October 17, 2012, issue of the journal Science Translational Medicine, the findings are based on the science of epigenetics. The insights into the complexities of gastric cancer could lead to better treatment approaches.
Gastric cancer is a heterogeneous disease with individual patients often displaying markedly different responses to the same treatment, according to Dr Patrick Tan of the Duke-NUS and lead author of the study. Like many cancers, gastric cancer is caused by genetic mutations, but also by external factors that affect the way genes work. These factors, called epigenetic alterations, work by methylation, a chemical process in which specific locations along the DNA (CpG sites) are modified through the addition of a methyl group. Methylation silences a gene's behaviour without actually altering the DNA sequence.
Gastric cancer methylome
In their study, Tan and colleagues used 240 primary tumours and cell lines to conduct the first full survey of the DNA methylation landscape in gastric cancer, known as the methylome. Their goal was to identify new molecular subgroups of gastric cancer not caused by primary genetic mutations, particularly those that might be targeted with therapies. The researchers found that the gastric cancer methylome was widespread, with more than half of the CpG sites analysed demonstrating altered methylation patterns in cancer. Many of the methylation alterations were associated with significant changes in gene expression, suggesting that the methylation alterations may be functionally important in the development of gastric cancer.
The researchers also identified a subgroup of gastric cancers with extremely high levels of methylation. The CIMP subgroup (CpG Island Methylator Phenotype) had been previously proposed, but its clinical significance remained unclear. The Duke-NUS-led team confirmed the CIMP subgroup, correlating it with younger patients who had a poor prognosis. They also demonstrated in laboratory experiments that these tumours may have increased sensitivity to demethylating drugs.
According to Dr Tan, this study does provide clarity in unambiguously demonstrating the presence of this subgroup and its features. There may be potential utility in testing the sensitivity of CIMP tumours to more potent DNA demethylating agents and possibly other epigenetic drugs.
The study also discovered long-range regions of epigenetic silencing, some targeting a generalised region and others that targeting a single gene. The finding may help identify novel genes where methylation events play a role in tumour growth.
The study results strongly demonstrate that gastric cancer is not one disease but a conglomerate of multiple diseases, each with a different underlying biology and hallmark features. Improving gastric cancer clinical outcomes will require molecular approaches capable of subdividing patients into biologically similar subgroups, and designing subtype-specific therapies for each group.
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