Stomach Cancer Subtypes Methylation-based identified by Singapore-Led Team

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Stomach Cancer Subtypes Methylation-based identified by Singapore-Led Team

October 17, 2012 by 2012pharmaceutical

Reporter: Aviva Lev-Ari, PhD, RN

Word Cloud By Danielle Smolyar

GASTRIC CANCER

Methylation Subtypes and Large-Scale Epigenetic Alterations in Gastric Cancer

+Author Affiliations

¹Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
²NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
³National Cancer Centre Singapore–Van Andel Research Institute Translational Research Laboratory, Department of Medical Sciences, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.
⁴Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁵Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore.
⁶Neuroscience and Behavioural Disorders, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
⁷Singapore-MIT Alliance, National University of Singapore, Singapore 119074, Singapore.
⁸Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore.
⁹Cancer Science Institute of Singapore, National University of Singapore, Singapore 119074, Singapore.
¹⁰National Cancer Institute Singapore, National University Hospital, Singapore 119228, Singapore.
¹¹Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
¹²Genome Institute of Singapore, 60 Biopolis Street, Genome 02-01, Singapore 138672, Singapore.

+Author Notes

↵* These authors contributed equally to this work.
↵† Present address: LabConnect, LLC, 2910 First Avenue South, Suite 200, Seattle, WA 98134, USA.

↵‡To whom correspondence should be addressed. E-mail: gmstanp@duke-nus.edu.sg

ABSTRACT

Epigenetic alterations are fundamental hallmarks of cancer genomes. We surveyed the landscape of DNA methylation alterations in gastric cancer by analyzing genome-wide CG dinucleotide (CpG) methylation profiles of 240 gastric cancers (203 tumors and 37 cell lines) and 94 matched normal gastric tissues. Cancer-specific epigenetic alterations were observed in 44% of CpGs, comprising both tumor hyper- and hypomethylation. Twenty-five percent of the methylation alterations were significantly associated with changes in tumor gene expression. Whereas most methylation-expression correlations were negative, several positively correlated methylation-expression interactions were also observed, associated with CpG sites exhibiting atypical transcription start site distances and gene body localization. Methylation clustering of the tumors revealed a CpG island methylator phenotype (CIMP) subgroup associated with widespread hypermethylation, young patient age, and adverse patient outcome in a disease stage–independent manner. CIMP cell lines displayed sensitivity to 5-aza-2′-deoxycytidine, a clinically approved demethylating drug. We also identified long-range regions of epigenetic silencing (LRESs) in CIMP tumors. Combined analysis of the methylation, gene expression, and drug treatment data suggests that certain LRESs may silence specific genes within the region, rather than all genes. Finally, we discovered regions of long-range tumor hypomethylation, associated with increased chromosomal instability. Our results provide insights into the epigenetic impact of environmental and biological agents on gastric epithelial cells, which may contribute to cancer.

http://stm.sciencemag.org/content/4/156/156ra140

Sci Transl Med 17 October 2012:
Vol. 4, Issue 156, p. 156ra140
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3004504

Methylation-based Stomach Cancer Subtypes

October 17, 2012

By a GenomeWeb staff reporter

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.