Scientists may have pinpointed the cause of some forms of a rare cancer called gastrointestinal stromal tumors (GISTs), according to a new NCI-funded study. However, the culprit isn’t a harmful genetic mutation, as is typical for cancer, but changes in genes that don’t involve mutations—what are called epigenetic alterations. About 10% of people with GIST have a form of the disease known as SDH-deficient GIST. Tumors of this type are marked by widespread epigenetic alterations but, until now, it hasn’t been clear if these alterations caused the cancer and could be potential targets for treatment. The new study shows that, in tumors of some people with SDH-deficient GIST, epigenetic alterations turned up several cell-growth genes to such high levels that they drove cancer growth. What’s more, treatment with a combination of drugs that block the proteins made by those genes substantially slowed the growth of SDH-deficient GIST in mice, Bradley Bernstein, M.D., Ph.D., of Massachusetts General Hospital and the Broad Institute, and his colleagues reported October 16 in Nature. One of the drugs, sunitinib (Sutent), is used to treat another form of GIST. The other, infigratinib (also called BGJ398), is being tested in clinical trials of a few types of cancer. There are no effective drug treatments for SDH-deficient GIST, which typically develops in the stomachs of children and young adults, said John Glod, M.D., Ph.D., of NCI’s Pediatric Oncology Branch. After surgery to remove the tumor(s), most patients are carefully monitored for cancer growth, he explained. The study findings “have the potential to open up new avenues for therapeutic intervention…in this subset of GIST tumors,” said Ian Fingerman, Ph.D., a program director in the DNA and Chromosome Aberrations Branch of NCI’s Division of Cancer Biology. Neither Dr. Glod nor Dr. Fingerman was involved in the study.