An interdisciplinary group of researchers from around the country analyzed tumor samples from nearly 10,000 patients with 34 types of cancer to reveal unique genetic switches associated with each tumor type. The research, published in Science Advances and supported by multiple OCRA grants, turned up three potential drug targets for aggressive ovarian cancer, among other findings.
Scientists know that mutations in individual genes can predispose people to cancer. But those same genes can also be switched on or off due to changes to transcription factors, stretches of DNA that regulate many genes at once, like fuses controlling many electric outlets. Researchers studying cancer cells often find altered “master transcription factors” (MTFs), which themselves control many transcription factors. Flipping an MTF on or off can affect dozens of genes at once, leading to drastic changes to a cell’s biology—in some cases, this could spur the development of cancer. Drugs targeting MTFs have been suggested as a way to treat cancers.
Pinning down which MTFs are related to cancer, however, can be tricky. Even in a healthy person, different MTFs are active in different cell types. In the past, researchers wanting to study the MTFs linked to a tumor relied on methods that required lots of very similar tumor cells—something not possible in all cancer types, particularly rare cancers like ovarian.
In the new study, researchers led by OCRA grantee Kate Lawrenson of Cedars-Sinai Medical Center developed a new approach to finding cancer-associated MTFs by comparing genetic data from many different types of cancer cells. The research team also included OCRA grantees Beth Karlan of UCLA, Isaac Klein of Dana-Farber Cancer Institute, and Danielle Chaves-Moreira of the University of Pennsylvania, as well collaborators from MIT, UCLA and St. Jude Children’s Research Hospital.
The researchers used the method, called Cancer Core Transcription Factor Specificity (CaCTS), to analyze samples from 9,691 patients with 34 tumor types collected in The Cancer Genome Atlas. The team homed in on 273 transcription factors—an average of 8 per cancer type—that appeared uniquely poised to play vital roles in tumor development. In cancer cells, they found, those MTFs were more likely to have mutations in them than other regions of DNA, underpinning their importance.
In high grade serous ovarian cancers, the CaCTS method identified 14 relevant MTFs, including some never before linked to ovarian cancer. Five of the MTFs, Lawrenson and her colleagues discovered, were required for some ovarian cancer cells to survive in culture dishes in the lab; this suggests that drugs targeting these transcription factors might help combat tumor growth.
Read the paper “Predicting master transcription factors from pan-cancer expression data” in Science Advances.