Environmental Factor, July 2008, National Institute of Environmental Health Sciences
Epigenetic Changes May Be Early Indicators of Cancer
By Dixie-Ann Sawin
A recent NIEHS-funded study headed by Stephen B. Baylin, M.D., at The Johns Hopkins Kimmel Cancer Center in Baltimore, Md., adds to the evidence that mutation and epigenetic phenomena in common genes may be early prognosticators of cancer. This study, published in PLoS Medicine, has important implications that may improve early detection or impact treatment outcomes.
The authors of the study (http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0050114) state that it is very unlikely for a given gene in breast and/or colon cancer to have mutations, hypermethylation and reduced expression and be localized to cancer mutation "hotspots" without also being important for tumor development. Working with this hypothesis, the researchers used an initial microarray strategy to screen a large pool of genes that bear low incidence heterozygous missense mutations for hypermethylation and expression status. Their aim was to identify genes that may have potential prognostic value.
The researchers used an unbiased genome-wide microarray approach to analyze potential gene targets of mutation and hypermethylation in breast and colon cancer cell lines and tumor tissue. Hypermethylation of CpG islands is an epigenetic silencing mechanism that is prevalent in cancer progression.
The team found that 56 out of 189 were potential candidate hypermethylated genes. Of these 56, they determined that 36 were in fact hypermethylated. They further determined that half of these were methylated in cell lines only and the other 18 were methylated in primary tumor tissue but not normal tissue.
Of particular note, the researchers observed that genes mutated in colon cancer, but not in breast cancer, may be hypermethylated in breast cancer and not in colon cancer. They also found that mutation and methylation were not always mutually exclusive.
Using Gene Ontology classification, the team determined that a number of the 18 hypermethylated genes were involved in signal transduction, cell adhesion and motility. Six were potential tumor suppressor genes. Sixteen of these 18 genes mapped to loci that were deleted in various cancers.
With regard to diagnosis of cancer, tumor stage and grade are among the strongest indicators of survival and propensity for metastasis in breast and colon cancer. Thus, the researchers sought to determine whether the expression of these genes could correlate to any of those indicators.
What they found was intriguing. Decreased expression levels of seven genes were associated with "unfavorable clinical characteristics in breast, colon cancer, or both." Decreased expression of five of these genes was associated with decreased survival, and four genes showed decreased expression with increasing tumor grade.
The researchers acknowledged that there are limitations to their study in that they did not address the biological effects of the individual mutations and that their data uses only 13,023 previously sequenced genes. More have recently been identified.
Their results suggest that mutation and epigenetic events both contribute to breast and colon cancer development. Their study advances the large-scale analysis of genetic and epigenetic phenomena in the discovery of potential cancer candidate genes.
Citation: Chan TA, Glockner S, Yi JM, Chen W, Van Neste L, Cope L, Herman JG, Velculescu V, Schuebel KE, Ahuja N, Baylin SB. 2008. Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis. PLoS Med 5(5):e114.
(Dixie-Ann Sawin, Ph.D., is a post-doctoral research fellow in the Laboratory of Neurobiology/Neurotoxicology Group.)