By searching previously ignored regions of the genome, Columbia cancer researchers have found a multitude of new genetic mutations that cause a common type of lymphoma.
"Our findings not only show that these mutations can contribute to diffuse large B cell lymphoma, but they identify an approach that should be useful for the analysis of other types of tumors," says Riccardo Dalla-Favera, MD, director of the Institute for Cancer Genetics at Columbia University Vagelos College of Physicians and Surgeons, who led the study.
Areas of the non-coding genome-called super-enhancers-are mutated in more than 90% of DLBCL tumors and may be necessary to sustain the cancer.
Diffuse large B cell lymphoma (DLBCL) is the most common type of human hematologic malignancy and is fast-growing and aggressive. Although treatment can now cure about two thirds of patients, the remaining patients have poor outcomes and new treatment strategies are needed.
Up to now, what researchers knew about DLBCL was based on lymphoma-causing mutations found in the genome's protein-coding genes. It was a logical place to begin, since these genes contain the instructions (or code) for making proteins, which carry out most of a cell's functions.
But 98% of the human genome does not contain code for making proteins. Previously mischaracterized as "junk," non-coding DNA is now known to have many functions, including critical roles in the regulation of gene expression.
In the new study, the Columbia researchers found that certain areas of the non-coding genome-called super-enhancers-are mutated in more than 90% of DLBCL tumors and may be necessary to sustain the cancer. Super-enhancers control the expression of one or more genes in the same chromosome.
The mutated super-enhancers found in the new study activate several cancer-causing genes. The researchers provide evidence that the genetic correction of specific recurrent mutations within these distinct super-enhancers restored the regulation of the cancer-causing genes and led to tumor death, indicating that the tumor was dependent on the mutated super-enhancers.
The findings also reveal a new level of genetic complexity behind DLBCL that could help explain why this cancer has many different subtypes with diverse behaviors.
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Riccardo Dalla-Favera, MD, is the Percy and Joanne Uris Professor of Clinical Medicine and a professor in the Departments of Pathology & Cell Biology, Genetics & Development, and Microbiology & Immunology. He is the director of the Institute for Cancer Genetics and a member of the Herbert Irving Comprehensive Cancer Center.
The study, published in the journal Nature, is titled, "Super-enhancer hypermutation alters oncogene expression in B cell lymphoma."
The other contributors are: Elodie Bal (Columbia), Rahul Kumar (formerly at Columbia and currently at Indian Institute of Technology), Mohammad Hadigol (Rutgers University), Antony B. Holmes (Columbia), Laura K. Hilton (BC Cancer Research Centre), Jui Wan Loh (Rutgers), Kostiantyn Dreval (Simon Fraser University), Jasper C. H. Wong (BC Cancer Research Centre), Sofija Vlasevska (Columbia), Clarissa Corinaldesi (Columbia), Rajesh Kumar Soni (Columbia), Katia Basso (Columbia), Ryan D. Morin (Simon Fraser University), Hossein Khiabanian (Rutgers University), and Laura Pasqualucci (Columbia).
This study was supported by grants from the National Institutes of Health (R35-CA210105, R01-CA172492, and R01-CA233662), an Astra Zeneca Scholar Award, a Herbert Irving Comprehensive Cancer Center VELOCITY award, and a Translational Grant from the V Foundation.
Dr. Dalla-Favera is a member of the scientific advisory board of NeoGenomics and a consultant for AstraZeneca. The work reported in this paper is not related to the current activities of these companies.
