BAF Mutations Drive Cancer by Reshaping DNA Accessibility to CTCF

Researchers at Weill Cornell Medicine have identified a unifying mechanism for a family of mutations found in approximately 20% of human cancers. The study, published in Nature on October 28, 2026, demonstrates that these mutations drive malignancy by altering the accessibility of genes to a specific regulatory protein known as CTCF. By revealing how these genetic changes reshape the three-dimensional architecture of DNA, the findings offer a potential pathway for developing new therapeutic strategies across a variety of cancer types, including lymphoma, breast cancer, ovarian cancer, and liver cancer.

The investigation focused on the BAF complex, a protein complex that regulates gene activity within the cell nucleus. Mutations in the genes encoding subunits of this complex are present in diverse tumors, yet the common mechanism linking these broad cancer connections had previously remained elusive. The BAF complex consists of multiple subunits, which in humans are encoded by more than two dozen genes. For years, researchers have attempted to understand the mechanisms of these cancer-linked mutations by examining their effects in specific cell types or tissues, such as breast tissue in the case of BAF-mutant breast cancers. The challenge for the study team was to find a potential cancer-promoting effect occurring across many different cell types and tissue models.

Using multiple animal and cell models of BAF deficiency, the investigators found that the loss of BAF function leads to the opening of the wrapped, looped structure of DNA at myriad sites across the genome. This structural change allows a master gene-regulator protein called CTCF to bind at those sites. Dr. Cem Meydan, a co-corresponding author and assistant professor of research in systems and computational biomedicine at Weill Cornell Medicine, noted that the BAF complex is normally thought to make DNA more accessible. Therefore, the team expected its loss to have the opposite effect. Instead, the loss of BAF function made DNA more accessible to CTCF, with surprisingly far-reaching effects on the genome.

CTCF normally acts like a boundary marker, dividing DNA into separate neighborhoods and controlling which genes can interact with which regulatory proteins. When the BAF complex is lost, CTCF binding increases at thousands of sites across the genome. This leads to a widespread reshaping of the three-dimensional loops and folds of DNA. These changes disrupt the normal contacts between genes and the elements that regulate them, altering gene activity in a way that leads to faster cell division. This disruption of DNA organization serves as a common thread in multiple cancer types, providing a mechanistic explanation for the broad association between BAF mutations and malignancy.

The study included confirmatory evidence from mouse models and human patient data, which supported the role of CTCF in BAF-mutant cancers. The team found evidence that disruptions of CTCF are associated with better patient outcomes. Additionally, the scientists showed that two other protein complexes, known as PBAF and ISWI, work as key partners of CTCF. The deletion of these partners also blocks the effects of BAF mutations. These results point to CTCF, PBAF, and ISWI as potential targets for future therapies in cancers characterized by BAF mutations.

Dr. Darko Barisic, a co-corresponding author and assistant professor of cancer biology in medicine at Weill Cornell Medicine, stated that these findings help establish a unifying mechanism for one of the most common classes of cancer mutations. He also identified CTCF and its partner proteins as candidate therapeutic targets in these cancers. The other co-corresponding authors were Dr. Cem Meydan 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.

The research was supported in part by the National Cancer Institute, the National Institute of General Medical Sciences, and the National Institute of Neurological Disorders and Stroke, all part of the National Institutes of Health. Additional support was provided by the Leukemia Research Foundation, the Andrew McDonough B+ Foundation, LLS, the STARR Foundation, the Rita Allen Foundation, the Irma T. Hirschl/Monique Weill-Caulier Trust, the Simons Foundation, and the Tri-Institutional Stem Cell Initiative. Dr. Barisic is currently investigating in more detail what this extensive gain of CTCF does to the genome, with the hope of finding a drug that blocks this process before long.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Cem Meydan. This work represents a significant step in understanding the molecular underpinnings of common cancer mutations, offering a clear target for future therapeutic interventions.

Subject of Research: Mechanism of BAF mutations in cancer via CTCF-mediated DNA reshaping

Article Title: A unifying mechanism for cancer-driving mutations

Article References: A unifying mechanism for cancer-driving mutations. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: BAF complex, CTCF protein, DNA architecture, cancer mutations, Weill Cornell Medicine, Nature journal, gene regulation, lymphoma, breast cancer, ovarian cancer, liver cancer, PBAF complex, ISWI complex, genomic accessibility, therapeutic targets, Darko Barisic, Cem Meydan, Ari Melnick, Sonia Debek, Christopher R. Chin