TCGA Findings Spotlight Drivers for Colorectal Cancer

Through large-scale sequencing efforts, investigators in The Cancer Genome Atlas (TCGA) Research Network have uncovered numerous genomic aberrations involved in the development and progression of colorectal cancers—discoveries that have the potential to change clinical practice.

Involving more than 200 researchers, the study characterized the molecular differences in 224 colorectal tumor samples compared with normal DNA from the same patients, analyzing exome sequence, whole genome sequence, DNA copy number, promoter methylation, and mRNA and microRNA expression. The findings, reported in Nature in July, “provide a useful resource for understanding this deadly disease and identifying possibilities for treating it in a targeted way,” the researchers conclude.

“This isn't going to impact clinical care today,” says Charles Fuchs, MD, MPH, director of the gastrointestinal cancer center at Dana-Farber Cancer Institute in Boston and a member of the TCGA network. However, Fuchs stresses that looking at the full spectrum of molecular changes in a large number of samples is an essential first step in developing new therapies. “The strength of this paper is that they painstakingly collected tumors and systematically analyzed them in just about every way possible,” he says.

The researchers found that 16% of the tumors were hypermutated. One quarter of those tumors had defects in mismatch-repair genes; three quarters of them exhibited microsatellite instability, in which repeated sequences of DNA become unstable and change in length.

In the non-hypermutated tumors, 24 genes were mutated in a significant number of cases. Although some of the genes on that list were already known through previous research—namely APC, TP53, SMAD4, PIK3CA, and KRAS—the researchers also found frequent mutations in ARID1A, SOX9, and FAM123B.

Drugs targeting the products of some gene amplifications or dysregulated pathways are already in development. For example, IGF2 overexpression was found in 22% of the samples. “That was a surprise,” says principal investigator Raju Kucherlapati, PhD, professor of genetics and medicine at Harvard Medical School in Boston, MA. “We didn't know about IGF2 amplification in these tumors before.” IGF2 may activate the PI3K-AKT pathway, playing a role in cell proliferation. Agents targeting this pathway are currently being tested.

About 60% of the tumors were dysregulated in the RAS-RAF-MAPK pathway, for which MEK inhibitors are under development. Kucherlapati notes that some tumors displayed dysregulation in both the PI3K-AKT and RAS-RAF-MAPK pathways, suggesting that combination therapies targeting both of those pathways should be tested.

Among other notable findings, the WNT signaling pathway was dysregulated in about 95% of tumor samples, and about 95% of samples exhibited changes in MYC-regulated genes.

The results may help to launch clinical trials relatively soon for some patients. TCGA researchers found that 5% of the tumor samples showed ERBB2/HER2 amplification. Breast cancer patients with this genetic abnormality respond well to trastuzumab (Herceptin; Genentech), which might be effective in this subset of colorectal cancer patients.

“That's what's so exciting,” says Kucherlapati. “We're talking about not just one possible new therapy, but a multitude of new therapies.”