Study identifies common mechanism behind widespread cancer mutations

A family of mutations seen in about 20% of human cancers drives malignancy by changing the accessibility of genes to a particular regulatory protein, according to a study by Weill Cornell Medicine investigators. The findings suggest new therapeutic strategies for a variety of cancer types.

The study, published Oct. 28 in Nature, focused on a protein complex called the BAF complex, which regulates gene activity in the nucleus. Mutations in genes that encode subunits of this complex are found in tumors as different as lymphoma, breast cancer, ovarian cancer and liver cancer, but the common mechanism underlying this broad connection to cancers has been elusive. In the study, the scientists showed that these BAF mutations effectively allow the three-dimensional architecture of DNA to be reshaped extensively by a protein called CTCF. This shifts gene activity in a direction that promotes malignancy, but deleting CTCF in an animal model reverses the effect.

These findings help us establish a unifying mechanism for one of the most common classes of cancer mutations, and identify CTCF and its partner proteins as candidate therapeutic targets in these cancers."

Dr. Darko Barisic, study co-corresponding author, assistant professor of cancer biology in medicine and member of the Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine

The other co-corresponding authors were Dr. Cem Meydan, assistant professor of research in systems and computational biomedicine at Weill Cornell Medicine; and Dr. Ari Melnick, director of the Josep Carreras Leukaemia Research Institute in Barcelona. The study's first authors were Dr. Meydan and postdoctoral research associates Dr. Sonia Debek and Dr. Christopher R. Chin.

Investigators at Memorial Sloan Kettering Cancer Center and The Rockefeller University also collaborated on the study.

Disruption of DNA organization common thread in multiple cancer types

The BAF complex has multiple subunits, which in humans are encoded by more than two dozen genes. For years, researchers have tried to understand the mechanisms of its various cancer-linked mutations by looking at their effects in specific cell types or tissues, such as breast tissue in the case of BAF-mutant breast cancers.

"The challenge for us was to find a potential cancer-promoting effect occurring across many different cell types and tissue models," said Dr. Barisic, who is also the John P. Leonard, M.D./Gwirtzman Family Research Scholar in Lymphoma.

Ultimately, using multiple animal and cell models of BAF deficiency, they found one such effect: The loss of BAF function led to the opening of the wrapped, looped structure of DNA at myriad sites across the genome, allowing a master gene-regulator protein called CTCF to bind at those sites.

"We normally think of the BAF complex as making DNA more accessible, and so we expected its loss to have the opposite effect," Dr. Meydan said. "Instead, its loss made DNA more accessible to CTCF, with surprisingly far-reaching effects."

CTCF normally acts like a boundary marker, dividing DNA into separate neighborhoods and controlling which genes can talk to which regulatory proteins. When the BAF complex is lost, CTCF binding increases at thousands of sites across the genome and leads to a widespread reshaping of the three-dimensional loops and folds of DNA. These changes disrupt the normal contacts between genes and elements that regulate them and alter gene activity in a way that leads to faster cell division.

Finding suggests potential therapeutics

In mouse models and human patient data, the team found confirmatory evidence of CTCF's role in BAF-mutant cancers, including evidence that disruptions of CTCF are associated with better patient outcomes.

The scientists showed that two other protein complexes, known as PBAF and ISWI, work as key partners of CTCF, such that their deletion also blocks effects of BAF mutations.

The results thus point to CTCF, PBAF and ISWI as potential targets for future therapies in cancers with BAF mutations.

"We're currently investigating in more detail what this extensive gain of CTCF does to the genome, and we hope before long to find a drug that blocks this process," Dr. Barisic said.