Chromosomal Aberration Patterns of Aggressive B-Cell Lymphomas Closely Correlate with Molecularly Defined Disease Subtypes and Regional mRNA Expression. An Analysis of 213 Tumor Samples within the German MMML Network.

Recently, it has been demonstrated that aggressive B-cell non-Hodgkin lymphomas (B-NHL) split up into distinct subgroups such as molecular Burkitt (mBL) and molecular non-Burkitt lymphomas (non-mBL). The non-mBL group can further be devided in activated B-cell (ABC) and germinal center B-cell (GCB) like lymphomas. In the present investigation we aimed at unravelling correlations of single or multiple chromosomal imbalances, their respective regional mRNA gene expression levels and the above mentioned molecular subgroups. Aggressive B-NHL samples (n=255) were investigated within the German network project Molecular Mechanisms in Malignant Lymphomas (MMML). Data from genomic arrayCGH analysis were evaluable for 213 lymphoma cases. Consensus review diagnoses according to WHO criteria were: DLBCL (n=154), atypical BL (n=20), typical BL (n=15) and other aggressive B-NHL (n=24). For all cases gene expression analysis was done using the Affymetrix U133A GeneChip. FISH data were available for translocations involving the MYC locus and for t(14;18). Using arrayCGH, chromosomal gains in more than 10% of all cases have been identified on 18q(24.4%), 3q(19.8%), 1q(19.1%), 12q(16.7%) 2p(16.3 %), 7p and 7q(16.3%), 6p(13.2%) and 11q(12.5%). Deletions occurred most frequently on chromosome arm 6q(20.3%), 17p(15.4%), 9p(14.8%) and 8p(10%). Molecular BLs had significantly less chromosomal aberrations than non-mBLs but frequently show gains of chromosome arm 1q. Non-mBLs show higher genomic complexity and strikingly differing aberration patterns for GCB (more than 20% gains on 1q, 2p, 7q, 11q, 12q) and ABC (more than 20% gains on 3q, 9p, 18q, loss on 6q) type lymphomas. These findings were also supported by results of genomic clustering algorithms such as non negative matrix factorization. For a large number of recurrent chromosomal aberrations we were able to delineate minimal aberrant chromosomal regions and to correlate respective regional mRNA gene expression levels. Strong proportional correlations were found for gains of 18q21.1-q21.33 and losses of 6q21-q24.3. In conclusion, genomic aberration patterns closely correlate with distinct molecular subtypes of aggressive B-NHL. These aberration patterns might serve as surrogate markers providing diagnostic and prognostic information as well as a basis for targeted gene investigations and risk adapted therapy studies.