Diffuse large B-cell lymphoma is an aggressive form of non-Hodgkin lymphoma that represents 30% of newly diagnosed cases. DLBCL consists of different subtypes that vary biologically and differ significantly in their survival rates following chemotherapy. Among the subtypes, the germinal center B cell-like (GCB) subtype is more responsive to treatment than the activated B cell-like (ABC) subtype. The current standard of care for DLBCL, a combination chemotherapy including four drugs collectively known as CHOP, is able to cure 50% to 60% of patients. Gene activity, or expression, is a measure of the biological activity of a gene. According to an article published in the New England Journal of Medicine (2008;359:2313-2323), patterns of gene activity in a type of non-Hodgkin lymphoma has provided a better understanding of factors that contribute to the survival of patients treated for the disease. Determining the activity levels of all genes in lymphoma patients’ genomes allowed the research team to identify sets of genes in diffuse large B-cell lymphoma (DLBCL) that influenced the effectiveness of treatment. For the study, after thousands of genes in DLBCL tumors were analyzed. One signature, termed the germinal center B-cell signature, was expressed by malignant cells in the tumors and reflected whether the tumors were of the GCB or ABC DLBCL subtype. In contrast, the other two gene expression signatures reflected different activities of the non-malignant cells within the tumor microenvironment. One signature, termed stromal-1, was found in tumors that expressed genes involved in forming or modifying the extracellular matrix, the fibrous network of molecules between cells that regulates the structure and function of tissues. These tumors also contained many macrophages, a type of white blood cell. High expression of this signature was associated with good prognosis. Another signature, termed stromal-2, was present in DLBCL tumors that had abundant angiogenesis, the process whereby new blood vessels are formed. The stromal-2 signature was associated with poor prognosis. The authors used the data from these three gene expression signatures to create a mathematical formula. Using this formula, they found that it was possible to divide patients who had been treated with R-CHOP or CHOP chemotherapy alone into subgroups that had better or poorer survival. The International Prognostic Index (IPI), a predictive index used by physicians to evaluate patients with DLBCL, is based on clinical factors including age, stage of the tumor, and whether cancer has spread to other parts of the body. Combining the gene signature model with the IPI improved the predictive power of both models. According to the authors, the ability of a patient with DLBCL to be cured by current therapy can be predicted by looking at the pattern of gene activity in the tumor biopsy sample taken at diagnosis. The authors also suggested that in the near term, there is a need to incorporate gene expression profiling in clinical trials to allow researchers to standardize results according to the variety of DLBCL tumors included in the trial. In the longer term, new therapies will emerge that are tailored to the particular gene expression profile of a patient’s lymphoma.


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