By searching previously ignored regions of the genome, researchers have found a multitude of new genetic mutations that may contribute to diffuse large B-cell lymphoma (DLBCL). These findings were published by Bal et al in Nature.
“Our findings not only show that these mutations can contribute to DLBCL, but they identify an approach that should be useful for the analysis of other types of tumors,” said senior study author Riccardo Dalla-Favera, MD, Director of the Institute for Cancer Genetics at Columbia University Vagelos College of Physicians and Surgeons.
DLBCL is the most common type of human hematologic malignancy and is a fast-growing and aggressive disease. Although treatment can now cure about two-thirds of patients, the remaining patients have poor outcomes, and new treatment strategies are needed.
Up until 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,” noncoding DNA is now known to have many functions, including critical roles in the regulation of gene expression.
Exploring the Noncoding Genome
In the new study, researchers found that certain areas of the noncoding 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 provided 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.
The study authors concluded, “This pervasive super-enhancer mutational mechanism reveals a major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.”
Disclosure: This study was supported by grants from the National Institutes of Health, an AstraZeneca Scholar Award, a Herbert Irving Comprehensive Cancer Center VELOCITY award, and a Translational Grant from the V Foundation. For full disclosures of the study authors, visit nature.com.
