Abstract
Introduction: MCL is an aggressive NHL characterized by a t(11;14)(q13;q32). However this translocation alone cannot initiate lymphomagenesis and multiple secondary genomic alterations are necessary to induce the neoplastic phenotype. In addition, three distinct clinicopathologic subtypes of MCL (classic, blastoid, and leukemic) have been identified with differing prognosis. Secondary genomic alterations associated with each subtype have been poorly defined. Experimental
Design: Genomic profiles from a panel of MCL samples comprised of 20 classic, 5 leukemic (no nodal involvement), and 12 blastoid cases, were created using a tiling-resolution BAC array CGH platform. Alignment of profiles to identify regions of recurrent alteration was accomplished using a custom developed software package (SeeGH). In addition, specific genes were analyzed for copy number status. Statistically significant distributions were determined using Chi square and Fisher’s exact analyses.
Results: Twenty two regions of recurrent alteration were identified that were statistically different between subtypes (partial data in Table 1). As expected chromosome 9 losses were more prevalent in blastoid MCL. 13q34 losses were prevalent within classic and blastoid MCL, as opposed to leukemic MCL, which showed gains of this region. Analysis of biological pathways revealed that apoptotic signaling is not disrupted via copy number in a large portion of MCL cases (21%), while chromosomal instability genes show copy number disruption in 67% of MCL cases. Surprisingly, the glioblastoma pathway was preferentially disrupted in blastoid MCL (p=1.09x10−5), affecting all cases; whereas the p53 pathway was disrupted via copy number more often in leukemic MCL (p=0.0207).
Conclusions: Multiple genomic regions and cancer related genes show a differential pattern of altered copy number distribution between MCL subtypes. These regions and genes likely contribute to the different clinicopathologic subtypes of MCL cases.
Differential regions in MCL subtypes
| +/− . | chr. band . | size (Mb) . | clas% . | leuk% . | blast% . | enriched in . | deficient in . |
|---|---|---|---|---|---|---|---|
| − | 1q25.2-q31.2 | 15.50 | 0 | 20 | 33 | blast (p=0.03) | class (p=0.01) |
| − | 2q26.3 | 2.91 | 5 | 0 | 33 | blast (p=0.03) | |
| + | 3cent-p12.1 | 4.18 | 0 | 60 | 25 | leuk (p=0.02) | class (p=0.005) |
| + | 7q11.23 | 3.24 | 0 | 0 | 33 | blast (p=0.008) | class (p=0.04) |
| − | 9p21.3 | 1.02 | 10 | 20 | 83 | blast (p=0.00001) | class (p=0.002) |
| − | 9q21.13 | 1.10 | 5 | 40 | 75 | blast (p=0.0003) | class (p=0.0002) |
| − | 9q21.2-q31.1 | 22.87 | 5 | 40 | 67 | blast (p=0.001) | class (p=0.0007) |
| − | 9q31.1 | 0.83 | 0 | 40 | 67 | blast (p=0.0004) | class (p=0.00006) |
| − | 9q34.12-qter | 7.27 | 0 | 20 | 42 | blast (p=0.009) | class (p=0.005) |
| + | 10p12.2-p12.31 | 0.63 | 5 | 0 | 42 | blast (p=0.009) | |
| − | 13q34 | 1.69 | 40 | 0 | 75 | blast (p=0.03) | leuk (p=0.05) |
| − | 17p13.3-pter | 2.28 | 5 | 60 | 25 | leuk (p=0.04) | |
| − | 17p13.1 | 1.21 | 5 | 60 | 25 | leuk (p=0.04) |
| +/− . | chr. band . | size (Mb) . | clas% . | leuk% . | blast% . | enriched in . | deficient in . |
|---|---|---|---|---|---|---|---|
| − | 1q25.2-q31.2 | 15.50 | 0 | 20 | 33 | blast (p=0.03) | class (p=0.01) |
| − | 2q26.3 | 2.91 | 5 | 0 | 33 | blast (p=0.03) | |
| + | 3cent-p12.1 | 4.18 | 0 | 60 | 25 | leuk (p=0.02) | class (p=0.005) |
| + | 7q11.23 | 3.24 | 0 | 0 | 33 | blast (p=0.008) | class (p=0.04) |
| − | 9p21.3 | 1.02 | 10 | 20 | 83 | blast (p=0.00001) | class (p=0.002) |
| − | 9q21.13 | 1.10 | 5 | 40 | 75 | blast (p=0.0003) | class (p=0.0002) |
| − | 9q21.2-q31.1 | 22.87 | 5 | 40 | 67 | blast (p=0.001) | class (p=0.0007) |
| − | 9q31.1 | 0.83 | 0 | 40 | 67 | blast (p=0.0004) | class (p=0.00006) |
| − | 9q34.12-qter | 7.27 | 0 | 20 | 42 | blast (p=0.009) | class (p=0.005) |
| + | 10p12.2-p12.31 | 0.63 | 5 | 0 | 42 | blast (p=0.009) | |
| − | 13q34 | 1.69 | 40 | 0 | 75 | blast (p=0.03) | leuk (p=0.05) |
| − | 17p13.3-pter | 2.28 | 5 | 60 | 25 | leuk (p=0.04) | |
| − | 17p13.1 | 1.21 | 5 | 60 | 25 | leuk (p=0.04) |
Disclosure: No relevant conflicts of interest to declare.
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