Noncoding DNA Drives Cancer, Too

Mutated genes aren't the only culprits in cancer. A new study suggests that mutations in regulatory regions of the genome, which don't code for proteins but instead control gene expression, also promote tumor growth and spread.

Researchers have uncovered more than 200 cancer drivers, genes that spur tumor progression when they are mutated. To investigate whether mutations in regulatory regions also influence cancer development, a team led by Emmanouil Dermitzakis, PhD, and Halit Ongen, PhD, of the University of Geneva Medical School in Switzerland sequenced the RNA in healthy tissue and tumors from 103 patients with colorectal cancer.

The team then used allele-specific expression analysis, a standard approach for recognizing the effects of regulatory mutations that involves comparing the expression of the two alleles of a gene. If, for example, the two alleles are expressed at different levels in a tumor but at the same level in healthy tissue, researchers infer that a mutation in a regulatory region could have modified expression in the tumor.

“We identified genes whose regulation is changed in cancer to drive progression,” says Dermitzakis. Because he and and his colleagues had germline sequences for 90 of the patients, they were able to determine the origin of the cancer-driving regulatory mutations. They found 71 genes for which somatic mutations in a regulatory region led to changes in expression in colon cancer cells. This group of genes includes previously discovered drivers for multiple cancers including colorectal cancer, such as AXIN2 and TP53.

As the researchers reported in Nature, they were also able to pinpoint inherited mutations in noncoding regions that affected the expression of 376 genes.

Inherited and somatic mutations in regulatory regions would influence cancer development differently, Dermitzakis says. Somatic mutations occur during the patients' lifetimes and in rare cases drive cancer. In contrast, inherited mutations are present from the beginning of the patients' lives. The researchers found that many of these inherited variants affect only gene expression in tumors, suggesting that they normally are harmless but might become drivers when the cell becomes cancerous, probably in the presence of other cancer-promoting mutations.

Scientists had not previously taken a close look at the noncoding portion of the genome to determine whether variants in regulatory sequences contribute to cancer. One caveat is that the new study relies on statistical analysis to deduce a connection between noncoding variants and cancer. Researchers still need to demonstrate how these alterations foster the growth and spread of tumors. Dermitzakis and colleagues also plan to search for possible tumor-promoting regulatory variants in other cancer types.

If researchers confirm the physiological role of regulatory mutations in cancer, “it could change the way you think about therapy,” says Greg Gibson, PhD, of the Georgia Institute of Technology in Atlanta. Current treatments target the functions of abnormal proteins, but if the new findings prove correct, researchers should consider developing drugs to alter the levels of key driver proteins, he says.