Across the landscape of cancer genome studies over the last two decades, the two percent of the genome made up of protein–encoding genes has proven to be fertile ground for researchers. There, scientists have uncovered hundreds of cancer–driving mutations and other alterations that change proteins’ structure and function (or stop their production altogether), fueling development of dozens of targeted treatments across several tumor types.

The other 98 percent of the genome – the noncoding genome, which includes the regulatory regions that controls where and when genes are turned on and off – has been less forthcoming with its secrets in cancer, however. And not for a lack of interest.

“People have anticipated finding noncoding mutations in cancer for a long time,” said Esther Rheinbay, a postdoctoral fellow in the lab of institute member Gad Getz, who leads the Broad Cancer Program’s Cancer Genome Computational Analysis group and is director of bioinformatics at Massachusetts General Hospital's (MGH) Center for Cancer Research (CCR) and Department of Pathology. “There have been many studies over the last several years. But only one recurrent noncoding mutation has been validated for function.”

With a new study in the journal Nature, a large, international collaborative effort including Rheinbay, Getz, and other scientists from the MGH CCR and Dana–Farber Cancer Institute (DFCI), as well as researchers from Mexico, the Slim Initiative in Genomic Medicine for the Americas (SIGMA) and elsewhere, have chalked up a new success, showing that breast cancers hide potentially important mutations in the promoters of at least nine genes. (Promoters are noncoding stretches of DNA just before genes, where the cell’s DNA–reading machinery latches on to start the transcription process.)

In addition to highlighting several genes not previously thought to be involved in breast cancer, the team’s findings offer new insights into how one known cancer gene may help breast tumors thrive in the face of treatment.

Getz, Rheinbay, and their team applied their targeted assay to tumor tissue from 360 breast cancer patients, collected from hospitals in Mexico and Spain and a pair of biobanks. The resulting data revealed a list of nine genes with unusually high numbers of mutations in their promoters: FOXA1, TBC1D12, RMRP/CCDC107, NEAT1, LEPROTL1, ALDOA, ZNF143, CITED2, and CTNNB1.

“Each of these mutations is relatively rare,” Getz said. “But they appear at frequencies on par with individual coding mutations against which targeted treatments have been or are being developed.”

When Getz’s lab at MGH probed the mutated promoters’ functional consequences, they fell into two groups: those that increased their genes’ expression (as was the case for the FOXA1 and RMRP promoters), and those that reduced expression.

Despite the fact that promoters have little DNA compared to genes (meaning there is much less opportunity for mutations to arise in them), six of the promoters harbored mutation hotspots (single sites that were mutated very frequently). Plus, Getz added, “when we accounted for the size of these regions, we found that the promoter mutations had a cancer–driving power akin to that of coding mutations.”