Posted: September 4, 2012
TCGA Analysis Reveals New Insights about Colorectal Cancer
Sara Bloom Leeds
The American Cancer Society estimates that more than 143,000 new cases of colon and rectal cancers will be diagnosed in the United States alone in 2012, and together, they are the third most common cancers in both men and women, excluding skin cancers. Although they have both been referred to by the single term “colorectal carcinoma,” whether they were the same or different cancer types has long been a topic of discussion.
The Cancer Genome Atlas (TCGA) Research Network has completed a comprehensive characterization of the genomes of 224 cancerous colorectal tumors and matching germline samples, published on July 19th 2012 in the journal Nature. The study is one of the most in-depth investigations of its kind to date.
Non-Hypermutated Colon and Rectal Cancers are Indistinguishable at the Genomic Level
Initially, TCGA researchers considered colon and rectal cancers as distinct and examined each separately. However, they found that the two were remarkably similar on a genomic level, excluding hypermutated tumors that had abnormally high rates of genetic mutations. Patterns of similarity were found among copy number, expression profile, DNA methylation and miRNA changes.
Overall, 24 genes were significantly mutated, including two particular genes long-known to play a role in colorectal carcinoma- APC and TP53. Interestingly, the TCGA Research Network noted that these two genes were more frequently mutated in the non-hypermutated tumors than the hypermutated ones. This may suggest that hypermutated and non-hypermutated tumors develop differently on a genetic level.
The hypermutated tumors comprised 16 percent of the tumor samples studied. Three-quarters of these hypermutated tumors displayed the expected high level of microsatellite instability (MSI), which means that normally repeated sections of DNA (microsatellites) become mutated, and thus become longer or shorter than normal. The other quarter were primarily characterized by having mutations in somatic mismatch repair pathways. In addition, the hypermutated tumors were found predominantly in the right colon and were more commonly hypermethylated. However, there is currently no explanation for this phenomenon.
Among other findings, researchers identified 28 frequent deletion peaks, some of which spanned several genes, and 17 regions of substantial focal amplification. In addition, frequent mutations in the SOX9 gene were found to be associated with colorectal cancer, which had not been previously known; this gene is associated with intestinal stem cell differentiation.
Significant Alteration of the WNT Signaling Pathway in Colorectal Cancer
Cancer often contains signaling pathways that can become deregulated by various other genomic changes. One of the most common recurrent alterations found in colorectal cancer occurred in the WNT signaling pathway. In fact, 93 percent of the tumors had permutations in this pathway. Most often, these changes appeared in the APC tumor suppressor gene, which helps to prevent cancerous tumor growth, although there were 16 altered genes in this pathway altogether.
The WNT pathway is typically inactive in most normal cells. But, if it does become activated by a WNT protein binding with a ligand receptor called frizzled 10 (FZD10) on the cell’s surface, a complex cascade of events within the cell will lead to the production of proteins as well as the transcription factor, MYC. In cancer, this occurs without a WNT protein binding and may cause MYC to become overexpressed. Thus, the subsequent unregulated gene expression can lead to the formation of colorectal cancer. FZD10 was also found to be overexpressed in colorectal cancer, and in some instances at levels 100 times greater than normal.
Implications of TCGA’s Characterization of Colorectal Tumors
These findings may one day help drug developers to create medications and treatments that are better targeted at these specific abnormalities, essentially producing more focused, therapeutic approaches to treating colorectal carcinoma. The data can also serve as a useful resource for future studies.
The Cancer Genome Atlas Research Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487(7407): 330-337. Read the full article