Diffuse Large B-Cell Lymphoma Subgroups Have Distinct Genetic Profiles that Influence Tumor Biology and Improve Gene Expression-Based Survival Prediction for the Lymphoma/Leukemia Molecular Profiling Project

Gene expression profiling has identified three major subgroups of diffuse large B-cell lymphoma (DLBCL): germinal center B cell-like (GCB), activated B cell-like (ABC), and primary mediastinal DLBCL (PMBCL). Using comparative genomic hybridization (CGH) we investigated the genetic alterations of 224 untreated DLBCL (87 GCB-DLBCL, 77 ABC-DLBCL, 19 PMBCL, and 41 unclassified-DLBCL) previously characterized by gene expression profiling. The DLBCL subgroups differed significantly in the frequency of particular chromosomal aberrations. ABC-DLBCL had frequent trisomy 3, gains of 3q and 18q21-q22, and losses of 6q21-q22, whereas GCB-DLBCL had frequent gains of 12q12, and PMBCL gains of 9p21-pter and 2p14-p16. Parallel analysis of CGH alterations, locus-specific gene expression profiles and global gene expression signatures revealed that DNA amplifications and gains had a substantial impact on the expression of genes in the involved chromosomal regions, and some genes were overexpressed in a DLBCL subgroup-specific fashion. Unexpectedly, specific chromosomal alterations were associated with significant changes in gene expression signatures that reflect various aspects of lymphoma cell biology as well as the host response to the lymphoma. In addition, gains involving the chromosomal region 3p11-p12 provided prognostic information that was statistically independent of the previously defined gene expression-based survival model, thereby improving its predictive power.

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