A new study suggests that RNF43 is one of the most commonly mutated genes in endometrial and colorectal cancers and may help identify patients who could potentially benefit from drugs that target the Wnt signaling pathway.

Researchers have discovered a previously overlooked genetic mutation in almost 20% of colorectal and endometrial cancers that may help identify patients who could benefit from drugs targeting the Wnt signaling pathway.

Investigators conducting whole-exome sequencing of 185 colorectal cancer specimens unexpectedly encountered a high frequency of mutations in RNF43—an E3 ubiquitin–protein ligase that negatively regulates Wnt signaling—that had been missed in previous studies, including one by The Cancer Genome Atlas (TCGA). Suspecting that the mutations were inadvertently filtered out of the TCGA analysis, the researchers reanalyzed 222 TCGA colorectal cancer samples and 248 TCGA samples of endometrial cancer—which is also dependent on abnormal Wnt signaling—and found RNF43 mutations in 17.6% and 18.1% of cases, respectively.

The TCGA analysis may have confused some RNF43 alterations with polymerase slip errors, which can occur while samples are processed for sequencing, explains senior study author Levi Garraway, MD, PhD, an associate professor of medicine at Harvard Medical School, who is also affiliated with Dana-Farber Cancer Institute and Brigham and Women's Hospital, all in Boston, MA, and the Broad Institute in Cambridge, MA. TCGA's sequencing process may have labeled these mutations as false positives and filtered them out.

The study suggests not only that RNF43 is one of the most commonly mutated genes in endometrial and colorectal cancers but also that comprehensive searches in other types of tumors driven by abnormal Wnt signaling could yield valuable insights (Nat Genet 2014;46:1264–6). For example, RNF43 mutations also appear to play a significant role in tumors exhibiting microsatellite instability (MSI), such as some stomach cancers.

“Any cancer that has an MSI phenotype for which there is precedent for Wnt pathway dysregulation might be a place to look for RNF43 mutations,” says Garraway. Two recent studies reported RNF43 mutations in gastric cancer, with a higher percentage found in tumors with MSI.

Researchers also found that RNF43 mutations are more likely to be present in the absence of APC mutations, the most frequently mutated gene in colorectal cancer. “RNF43 mutations tend to occur in mutually exclusive patterns with other members of the Wnt signaling pathway, such as APC mutations,” says Garraway.

The study provides further evidence that tumors with mutant RNF43 may be uniquely sensitive to drugs that ­target the Wnt pathway, says Garraway. Small-molecule porcupine inhibitors that target Wnt signaling are currently being tested in clinical trials involving other malignancies with RNF43 mutations, such as pancreatic cancer. Given the mutated gene's significant role in colorectal and endometrial cancers, there may be broader indications for porcupine inhibitors than previously thought.

“The other exciting aspect of our findings is that RNF43 regulates the stability of the cell surface receptor complex that allows Wnt to signal,” says Garraway. “It suggests that blocking Wnt at the level of ligand production or receptor-based signaling may represent a therapeutic avenue.”

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