DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: A comprehensive profiling approach

10.1186/1471-230X-14-55BMC Gastroenterology141-BGMA

Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features

<p>Abstract</p> <p>Background</p> <p>Most previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites. In the present study we performed comprehensive DNA methylation profiling of CRC with the aim of characterizing CIMP subgroups.</p> <p>Methods</p> <p>DNA methylation at 1,505 CpG sites in 807 cancer-related genes was evaluated using the Illumina GoldenGate^®methylation array in 28 normal colonic mucosa and 91 consecutive CRC samples. Methylation data was analyzed using unsupervised hierarchical clustering. CIMP subgroups were compared for various clinicopathological and molecular features including patient age, tumor site, microsatellite instability (MSI), methylation at a consensus panel of CpG islands and mutations in <it>BRAF </it>and <it>KRAS</it>.</p> <p>Results</p> <p>A total of 202 CpG sites were differentially methylated between tumor and normal tissue. Unsupervised hierarchical clustering of methylation data from these sites revealed the existence of three CRC subgroups referred to as CIMP-low (CIMP-L, 21% of cases), CIMP-mid (CIMP-M, 14%) and CIMP-high (CIMP-H, 65%). In comparison to CIMP-L tumors, CIMP-H tumors were more often located in the proximal colon and showed more frequent mutation of <it>KRAS </it>and <it>BRAF </it>(<it>P </it>< 0.001).</p> <p>Conclusions</p> <p>Comprehensive DNA methylation profiling identified three CRC subgroups with distinctive clinicopathological and molecular features. This study suggests that both <it>KRAS </it>and <it>BRAF </it>mutations are involved with the CIMP-H pathway of CRC rather than with distinct CIMP subgroups.</p

Clinical Potential of DNA Methylation in Gastric Cancer: A Meta-Analysis

Background: Accumulating evidence indicates aberrant DNA methylation is involved in gastric tumourigenesis, suggesting it may be a useful clinical biomarker for the disease. The aim of this study was to consolidate and summarize published data on the potential of methylation in gastric cancer (GC) risk prediction, prognostication and prediction of treatment response. Methods: Relevant studies were identified from PubMed using a systematic search approach. Results were summarized by meta-analysis. Mantel-Haenszel odds ratios were computed for each methylation event assuming the random-effects model. Results: A review of 589 retrieved publications identified 415 relevant articles, including 143 case-control studies on gene methylation of 142 individual genes in GC clinical samples. A total of 77 genes were significantly differentially methylated between tumour and normal gastric tissue from GC subjects, of which data on 62 was derived from single studies. Methylation of 15, 4 and 7 genes in normal gastric tissue, plasma and serum respectively was significantly different in frequency between GC and non-cancer subjects. A prognostic significance was reported for 18 genes and predictive significance was reported for p16 methylation, although many inconsistent findings were also observed. No bias due to assay, use of fixed tissue or CpG sites analysed was detected, however a slight bias towards publication of positive findings was observed

Genes differentially methylated in case-control studies of normal tissue, serum and plasma from gastric cancer and non-cancer subjects.

1<p>Odds ratio (OR) describes the likelihood of gene methylation observed in samples from gastric cancer compared to non-cancer subjects. Only genes in which there were significant differences in methylation between the two groups are displayed (<i>p</i><0.05). Genes for which there was no significant difference are displayed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036275#pone.0036275.s004" target="_blank">Table S2</a>.</p

Flow diagram of the literature search strategy and assessment of studies identified for systematic review.

<p>Data from some studies was used in multiple meta-analyses, as they reported on more than one case-control analysis considered.</p

Summary of gene methylation and GC prognosis in the component studies.

1<p>The prognostic outcome was based on disease-free survival (DFS). The brackets displayed the p-value for studies that showed significance. NS: Not significant.</p

Genes differentially methylated in case-control studies of tumour and normal gastric tissue from GC subjects.

1<p>Odds ratio (OR) describes the likelihood of gene methylation observed in tumour compared to normal gastric tissue. Only the genes for which there was a significant difference in methylation frequency between the two groups are displayed (p<0.05). Genes for which there was no significant difference are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036275#pone.0036275.s003" target="_blank">Table S1</a>.</p