Researchers from the Dana-Farber Cancer Institute, MIT’s Broad Institute, and Harvard report that they have identified in about 20% of colorectal and endometrial cancers a genetic mutation that had been overlooked in recent large, comprehensive gene searches. With this discovery, the altered gene, called RNF43, now ranks as one of the most common mutations in the two cancer types, according to the team.
In a study (“RNF43 is frequently mutated in colorectal and endometrial cancers”) published in Nature Genetics, the researchers said the mutated gene helps control an important cell-signaling pathway, Wnt, that has been implicated in many forms of cancer. They suggest that the RNF43 mutation may serve as a biomarker that identifies patients with colorectal and endometrial cancer who could benefit from precision cancer drugs that target the Wnt pathway, although no such drugs are currently available.
“Tumors that have this mutation may be telling us that they are dependent on the Wnt signaling pathway, and they will be uniquely sensitive to drugs that inhibit this pathway,” said Charles Fuchs, M.D., an author of the paper and director of the Center for Gastrointestinal Cancer at Dana-Farber. He is also affiliated with Brigham and Women's Hospital and the Harvard School of Public Health.
In animal models of cancer, tumors that harbor RNF43 mutations have been found to be sensitive to new Wnt pathway inhibitors that are now in clinical trials in humans, according to Marios Giannakis, M.D., Ph.D., who is affiliated with Dana-Farber and is also a postdoctoral researcher at the Broad Institute.
The researchers were surprised to find RNF43 mutations in such a significant proportion of colorectal and endometrial cancers because they had not been detected in recent comprehensive searches of tumor DNA conducted by scientists of The Cancer Genome Atlas (TGCA) project.
“We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas,” wrote the investigators. “RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers.”
Authors of the new study believe computer algorithms used by TCGA to parse data from DNA sequencing of tumors may have interpreted the “signal” of the RNF45 mutation as an artifact, and discarded it, much as a legitimate email will sometimes be trapped in a junk filter.
“These mutations occur in repetitive regions of the genome where you often have errors in DNA sequencing, so the algorithm may have been more likely to assume that the RNF43 mutation was an artifact of the sequencing process,” explained Eran Hodis, an M.D./Ph.D. student at Harvard Medical School and MIT and also affiliated with the Broad and Dana-Farber. Giannakis and Hodis are co-first authors on the new report.
The study authors noted that the discovery of such a significant cancer mutation that hadn't been picked up in the previous gene hunts shows that carrying out these comprehensive genomic searches continues to have value.