Mantle Cell Lymphoma Genotypes Identified with CGH to BAC Microarrays Define Clinical Subgroups of Disease and Strongly Predict Patient Outcome.

Mantle cell lymphoma (MCL) is a rare, aggressive subtype of B-cell non-Hodgkin lymphoma (B-NHL), characterized by t(11;14)(q13;q32). To identify recurrent genomic events involved in the pathogenesis of this malignancy, we used genome-wide comparative genomic hybridization (CGH) to 1.4 Mb. resolution BAC microarrays in 68 patients and 9 derived MCL cell lines; the genome profiles were compared to those from other B-NHL subtypes. Array-CGH defined a MCL genomic signature different from other B-cell lymphomas, including deletions of chromosomes 1p21.2-p12.3, 11q22.3 at ATM gene locus, 13q14.2 and 13q34, with coincident 10p12-BMI locus amplification and 10p14 deletion, along with a previously unidentified loss within 9q21-q22. Specific genomic alterations were associated with different subgroups of disease. Notably, 11 patients with non-nodal, leukemic MCL, defined on the basis of the absence at diagnosis of lymph node disease, showed a different genomic profile to nodal cases, including deletion of 8p21.2 at TRAIL receptor gene cluster (55 vs. 19%;p=0,01) and gain of 8q24.1 at MYC locus (46 vs. 14%;p=0,015). Additionally, leukemic MCL exhibited frequent IgV_H mutation (64 vs. 21%;p=0,009) with preferential VH-39 use (36 vs. 4%;p=0,005), and followed a more indolent course, being 7 of 11 patients (64%) survivors for more than 3 years whereas only 15 of 55 patients (27%) in the nodal group experienced this long survival (median survial time, 42 vs. 18 months; p=0,02). The median overall survival (OS) for the patients in the series was 39 months (range, 0–115). Blastoid variant of MCL, increased number of genomic gains, and deletions of P16/INK4a and P53 genes correlated with poorer outcomes, whilst 1p21 loss was associated with prolonged survival (median OS, 70 vs. 31 months; p=0,02). In multivariate analysis, deletion of chromosome 9q21-q22, which has not been previously reported as a common change in MCL, was the strongest predictor for inferior survival (HR:6; CI:2,3–15,7). Last, the genotypes of 14 patients with MCL who were alive for more than 5 years since diagnosis showed deletion of 1p21 in seven cases (50%), but none exhibited deletions of 9q21-q22, 9p21.3-P16/INK4a or 17p13.1-P53. Our study illustrates the utility of array-CGH in MCL sub-classification and highlights the array genomic profile as the strongest indicator for predicting clinical outcome. The screening of this reduced BAC clone set either by FISH or custom-made array CGH devices could be reliably applied to the clinical diagnostics of MCL.