October 26, 2014
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Novel mutation detected in nearly 20% of colorectal, endometrial cancers

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Somatic mutations of RNF43 were detected in nearly one of every five colorectal cancers and endometrial cancers, a finding that suggests the novel mutation is one of the most frequent in these cancers, according to study results.

Marios Giannakis, MD, PhD, instructor in medicine at Dana-Farber Cancer Institute and researcher at the Broad Institute of MIT and Harvard, and colleagues conducted whole-exome sequencing on 185 colorectal tumor and matched DNA samples from participants in the Nurses’ Health Study and the Health Professionals Follow-up Study.

Overall, 18.9% of the samples harbored RNF43 mutations, which encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. The frameshift mutation G659fs accounted for 41.7% of the RNF43 mutations, whereas R117fs frameshift mutations accounted for 8.3% of the mutations.

Previous studies of similar scale — including one conducted by The Cancer Genome Atlas (TCGA) that evaluated 224 colorectal tumor samples — did not show the same high frequency of RNF43 mutations.

Giannakis and colleagues hypothesized that the TCGA study did not detect the mutation due to the similarity of RNF43 frameshift events with polymerase slip errors that may have caused them to be inadvertently filtered out of the analysis. Giannakis and colleagues re-analyzed 222 of these samples and detected RNF43 mutations in 17.6% of them.

Because endometrial cancer is another disease dependent upon Wnt signaling, Giannakis and colleagues also re-evaluated 248 endometrial tumor and normal exome pairs from the TCGA study. Of these samples, 18.1% harbored a non-silent RNF43 mutation. The G659fs variant accounted for 47.3% of these mutations, and the R117fs frameshift accounted for 3.6% of the mutations.

Charles S. Fuchs, MD

Charles Fuchs

Researchers also identified RNF43 mutations in 79.7% of microsatellite instability-high colorectal tumors and 50.7% of microsatellite instability-high endometrial tumors.

Although no agent yet targets the Wnt signaling pathway, the detection of this mutation holds promise for future treatment options, researchers said.

“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,” researcher Charles Fuchs, MD, MPH, director of the Center for Gastrointestinal Cancer at Dana-Farber Cancer Institute, said in a press release.

Disclosure: One researcher reports consultant roles with Boehringer Ingelheim, Foundation Medicine, Millennium/Takeda and Novartis, as well as grant support from Novartis.