Molecular diagnosis and outcome prediction in lymphoma

Division Of Basic Sciences - Nci

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Abstract

On the basis of gene expression profiling, the laboratory proposed that the most common form of lymphoma, diffuse large B cell lymphoma (DLBCL), is a composite of three molecularly distinct diseases that are indistinguishable by standard diagnostic methods. These diseases, termed germinal center B cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal B cell lymphoma (PMBL), arise from B lymphocytes at different stages of differentiation by distinct oncogenic pathways. The curative response of patients with DLBCL to chemotherapy is highly variable, and the DLBCL subtype distinction accounts, in part, for this heterogeneity. With CHOP multi-agent chemotherapy, the 5-year survival rates of ABC DLBCL and GCB DLBCL are 60% and 30%, respectively. This clinical disparity likely reflects the host of genetic differences between these DLBCL subtypes. Array-based comparative genomic hybridization was used to identify genomic changes in copy number that influenced survival. Two genomic alterations that occurred exclusively in ABC DLBCL were deletion of the INK4a/ARF tumor suppressor locus and trisomy 3. These genetic aberrations, considered separately and together, identified a subset of patients with ABC DLBCL with inferior prognosis relative to other patients with this DLBCL subtype. This ABC DLBCL subset was also characterized by oncogenic mutations in the CARD11 gene, which encodes a scaffold molecule required for NF-kB signaling downstream of the B cell receptor. These mutations are responsible for constitutive NF-kB activity in ABC DLBCLs. The co-occurrence of CARD11 mutations, INK4a/ARF locus deletions and trisomy 3 in a subset of ABC DLBCLs suggests that this subset may arise by a distinct pathogenetic pathway. Mantle cell lymphoma is a disease with a highly variable clinical course, with some patients living 5 or more years and other succumbing to the disease in under 1 year. The Staudt laboratory previously discovered that a gene expression signature of cellular proliferation was the single dominant predictor of length of survival following diagnosis of mantle cell lymphoma. One mechanism responsible for the increased proliferation of some mantle cell lymphoma tumors is increased expression of cyclin D1, which is characteristically translocated in this disease. The Staudt laboratory demonstrated that variability in cyclin D1 mRNA in mantle cell lymphoma was due to somatic alterations in the 3 untranslated region (UTR) of the mRNA. The 3UTR of cyclin D1 contains a sequence that destabilizes the cyclin D1 mRNA. The Staudt laboratory deletions encompassing this region in some cases with high cyclin D1 mRNA expression. A novel form of somatic mutation was identified in other such cases in which point mutations following the stop codon created new polyadenylation and cleavage signals, resulting in expression of a short cyclin D1 mRNA lacking the destabilization motif. As expected, these short cyclin D1 mRNAs accumulated to higher levels due to their prolonged half-life.