Integrated CGH- and Epression Array Profiling of Mantle Cell Lymphoma.

Abstract

Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14)(q13;q32), which leads to the overexpression of cyclin D1. The cyclin D1-overexpression by itself is however not sufficient for lymphoma development. To identify other genes that are deregulated in MCL, we have performed integrated profiling of high-resolution array-based comparative genomic hybridization (array-CGH) with RNA-expression array analysis on the same set of MCL cases. DNA-alterations of MCL cases were assessed using a 3.6k BAC array with a resolution of 800 kb. On the same cases, RNA-expression array analysis was performed using the GeneChip® Human Genome U133 Plus 2.0 Array from Affymetrix. Integration of genomic-and transcription profiling data was performed using statistical tools. With array-CGH, we identified regions of chromosomal gain or loss and determined minimal common regions (mcr's) by identifying the smallest region of overlap present in at least 36% of the cases. Integration of array-CGH and expression profiling was performed for genes located within the mcr's and unsupervised clustering of gene-expression values within each mcr was performed. For several mcr's, e.g. 1p22.1–31.1, 6q23.2–27 and 11q22.3–23.3, the clustering tree showed two groups, one with the chromosomal aberration and one without. Also, we observed that only a subset of genes located within a cytogenetic anomaly has a concomitant change in mRNA expression level. These genes are regulated by DNA-copy number (gene dosage). Amongst these, we identified several “hypothetical genes” and genes, which encode proteins involved in mitochondrial protein synthesis, the DNA damage repair pathway and the cAMP regulated pathway. This study shows the potential of the integrated profiling approach for identifying genes that are regulated by gene dosage (DNA-copy number). We anticipate that the genes we identified are important for MCL and it's characteristic features like the low apoptosis rate and the chemotherapy-resistance.