Clinical translation of gene expression profiling in lymphomas and leukemias

Current lymphoma classification schemes that incorporate information on immunophenotype and genetic aberrations of the neoplastic cells represent a first attempt at a molecular diagnosis of these malignancies. Gene expression profiling using DNA microarrays promises to dramatically enhance molecular diagnosis by quantitating gene expression in tumor cells on a genomic scale. In this review, we focus on recent studies of diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) that illustrate the effectiveness of gene expression profiling in defining molecularly distinct diseases. In DLBCL, germinal center B-like (GCB) and activated B-cell-like (ABC) subgroups differ in the expression of more than 1,000 genes and have a markedly different clinical outcome, suggesting that this diagnostic category includes at least two distinct molecular diseases. In CLL, by contrast, all cases express a characteristic set of genes, suggesting that CLL should be considered a single disease. Nonetheless, two subtypes of CLL exist that are distinguished by the presence or absence of immunoglobulin gene mutations, by the expression of approximately 175 genes, and by clinical course. Clinical translation of these results should be implemented initially in clinical trials where gene expression profiles could identify subsets of patients that are particularly responsive to the therapies being evaluated. As the armamentarium of molecularly targeted therapies expands, molecular diagnosis will be seen as an integral component of clinical management.