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Methylation Subtypes and Large-Scale Epigenetic Alterations in Gastric Cancer

NEW YORK (GenomeWeb News) – A new study in Science Translational Medicine is highlighting the epigenetic subtypes that exist within stomach cancer.

“Our 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,” senior author Patrick Tan, a cancer researcher with the Duke-National University of Singapore Graduate Medical School, said in a statement.

“If gastric cancer is the result of multiple interacting factors, including both environmental factors and host genetic factors, we need better ways to diagnosis and treat it,” added Tan, who is also affiliated with Singapore’s National Cancer Centre and the Genome Institute of Singapore.

Tan and colleagues based in Singapore and the US did array-based DNA methylation analyses on more than 200 gastric tumors and dozens of gastric cancer lines. Their subsequent analyses of these methylation profiles indicated that stomach cancers have many stretches of sequence with higher or lower levels of methylation compared with nearly 100 matched normal stomach samples.

Within the tumor and cell lines, the analysis revealed subsets of gastric cancer with distinct methylation profiles that appear to be prognostically important.

In particular, a group of tumors known as CIMP (CpG island methylator phenotype) tumors, which show excess methylation at some cytosine and guanine-rich regions of the genome, tended to turn up in younger gastric cancer patients and those with poor outcomes.

On the other hand, results of the study also hint that the pronounced methylation shifts in these CIMP gastric cancers could also render them more vulnerable to demethylating compounds.

“Gastric cancer is a heterogenous disease with individual patients often displaying markedly different responses to the same treatment,” Tan said. “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.”

Previous genomic studies have started to unravel the range of somatic mutations and other genetic alterations that can contribute to gastric adenocarcinoma, the researchers noted. Less is known about the epigenetic features of the often deadly disease, which is especially common in some Asian populations, though some studies have identified specific genes with unusual epigenetic profiles in gastric cancer.

In an effort to more fully understand the epigenetic features of stomach cancer, Tan and his colleagues used Illumina Infinium arrays to profile cytosine methylation patterns in tumor samples from 203 individuals with gastric cancer, along with matched normal stomach tissue samples for 94 of the patients.

Using a similar strategy, the group also measured genome-wide methylation patterns in 37 stomach cancer cell lines.

When they compared methylation profiles across the samples, the researchers saw that some 44 percent of the CpG sites tested had higher- or lower-than-usual cytosine methylation levels that were specific to the stomach cancer. Around a quarter of these seemed to coincide with either jumps or — more frequently — dips in gene expression in the tumors, they reported.

A subset of the tumors had especially high levels of CpG island methylation, the team found. Follow-up analyses indicated that these tumors — which comprise an apparent CIMP sub-group of the stomach cancer — were more commonly found in young patients and/or those with poor survival outcomes.

Over-represented amongst the genes in highly methylated regions of CIMP tumors were genes implicated in stem cell-related processes, researchers noted, as were sites recognized by the histone regulating Polycomb repressive complex.

“Taken collectively,” they wrote, “these results suggest that CIMP tumors may represent a clinically and biologically distinct sub-group of gastric cancers.”

Moreover, in one of its follow-up experiments the team found that it was possible to curb the proliferation of seven gastric cancer-derived cell lines in the CIMP sub-group using a demethylating drug called 5-aza-2′-deoxycytidine, or 5-Aza-dC — an effect they did not see in 10 non-CIMP cell lines treated with the drug.

Based on findings from their methylation and gene expression profiling in gastric cancer so far, the study authors argued that an improved appreciation of the methylome-based sub-types present in the disease might aid future efforts to improve stomach cancer diagnosis and treatment options.

“[A]dditional work will focus on developing simple diagnostic tests to detect gastric cancer at earlier stages, plus drugs and drug targets that might exhibit high potency against different molecular subtypes of disease,” Tan said in a statement.