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Mapping the Molecular Changes in Colorectal Cancer

A molecular analysis of colon and rectal tumors has yielded insights that could lead to more targeted treatments for patients with this disease, according to a report by investigators from The Cancer Genome Atlas (TCGA) Research Network. Their findings are publicly available (here and here) and summarized in Nature this month. TCGA investigators have previously reported on the molecular changes underlying ovarian cancer and glioblastoma, an often deadly brain cancer. In the new analysis, the researchers comprehensively characterized the genomes of 224 colon or rectal tumors, as well as matched normal DNA from the donors.

After excluding from their analysis tumors that had abnormally high rates of genetic mutation (hypermutated tumors), the researchers found no significant genomic differences between colon and rectal tumors, based on a variety of measures, including the number of copies of genes and the gene expression profiles of the tumors. But an analysis of the molecular pathways in colorectal tumors showed that pathways could be disrupted in a number of ways. Some tumors had potentially cancer-related changes in multiple pathways, suggesting to the researchers that targeting a single pathway would not be sufficient to treat these tumors.

Most of the approved treatments for colorectal cancer are chemotherapies that produce poor response rates, noted Dr. Raju Kucherlapati of Harvard Medical School, who co-led the study. The new findings could form the basis for developing and testing therapies that target the molecular changes driving the disease, he added.

"There are a number of genetic changes present [in the tumors we examined], and drugs that target many of these changes are already in development," Dr. Kucherlapati continued. For selected patients, new targeted drugs "have the potential to be highly effective."

He and his colleagues in the TCGA Research Network also found that 16 percent of the tumors were hypermutated. This phenomenon may be caused by defects in a cell's ability to repair damaged DNA. Hypermutated tumors may also be aggressive.

Three-quarters of the specimens had a genetic change called microsatellite instability, which is associated with a better prognosis.

The researchers also found that the gene IGF2, which plays a role in cell proliferation, was altered in some tumors. Drugs that target the product of this gene or its receptor are in development and could be tested in patients whose tumors have alterations in IGF2.

The data from this study "provide an unprecedented resource for understanding this deadly disease and identifying possibilities for treating it in a targeted way," the authors concluded.

This research was supported by grants from the National Institutes of Health (U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, U24CA144025, U54HG003067, U54HG003079, and U54HG003273).