A genome-scale analysis of 276 colorectal cancer (CRC) samples has identified genetic vulnerabilities that a research consortium hopes will emerge as targets for new treatments against the disease.
In study results published online Wednesday in Nature, The Cancer Genome Atlas (TCGA) Network concluded that cancers of the colon and rectum can be grouped as one, since the pattern of genomic alterations in colon and rectal tissues is the same regardless of anatomic location or origin within the colon or the rectum. The TCGA network initially studied colon tumors as distinct from rectal tumors.
“This finding of the true genetic nature of colon and rectal cancers is an important achievement in our quest to understand the foundations of this disease,” NIH Director Francis S. Collins, M.D., Ph.D., said in a statement. “The data and knowledge gained here have the potential to change the way we diagnose and treat certain cancers.”
Two NIH institutes funded the study: the National Cancer Institute, and the National Human Genome Research Institute.
The consortium carried out analyses of the exome sequence, DNA copy number, promoter methylation, and messenger RNA and microRNA expression of the colorectal cancer samples, comparing results with healthy cells from the same patients.
In 224 of the colorectal cancer specimens examined, 24 genes were mutated in a significant number of cases. Building on past research that found several genes potentially driving CRC when mutated—including APC, ARID1A, FAM123B/WTX, TP53, SMAD4, PIK3CA, and KRAS—TCGA network researchers added to that list three other genes, ARID1A, SOX9, and FAM123B/WTX. Of the samples studied, 16% were hypermutated, with three-fourths of those samples showing high microsatellite instability, usually with hypermethylation and MLH1 silencing.
"[T]he data presented here provide a useful resource for understanding this deadly disease and identifying possibilities for treating it in a targeted way," corresponding author Raju Kucherlapati, Ph.D., principal investigator for the colon cancer project and a professor of genetics and of medicine at Harvard Medical School, joined colleagues in concluding.
“Our data suggest a number of therapeutic approaches to CRC. Included are WNT-signalling inhibitors and small-molecule β-catenin inhibitors, which are showing initial promise. We find that several proteins in the RTK-RAS and PI3K pathways including IGF2, IGFR, ERBB2, ERBB3, MEK, AKT, and MTOR could be targets for inhibition,” Dr. Kucherlapati and colleagues added.
Another co-author, Sanford Markowitz, M.D., Ph.D., of Case Western Reserve University, whose research focuses on colon cancer and genomics, told The New York Times that, while the TCGA network study offered more information on CRC than past, more limited studies, research remained at an early stage, “like sending out Lewis and Clark.”
The study is among recent examples of research to show that medicines designed to target gene mutations in one cancer may be applied to other malignancies with the same abnormality. Several pharma giants—including Bristol-Myers Squibb, Pfizer, and Roche—have focused their cancer research on such targeted therapies.