[Analysis of genomic copy number alterations of malignant lymphomas and its application for diagnosis]

Abstract

Array-based comparative genomic hybridization (array CGH) enables us to detect the genomic copy number alterations of cancers with high resolution. Our established array CGH platform consists of 2,304 BAC/PAC clones covering the whole genome at 1.3-mega base resolutions. Using this technique, we were thus able to reveal disease-specific genomic alterations and the candidate target genes in various lymphomas. We herein report the characteristic genomic alterations of malignant lymphomas including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and adult T cell lymphoma/leukemia (ATLL). The combined use of the array CGH data with gene expression profiling and specific gene rearrangement analyses further delineated the subtype-specific genomic alterations. For instance, we revealed that activated B-cell-like DLBCL is characterized by a gain of chromosome 3, 18q and loss of 9 p21, whereas the germinal center B-cell-like DLBCL is characterized by a gain of 2p15, 7q, and 12q. Among these genomic alterations,we found the 9 p21 loss (p16INK4a locus) to be the most aggressive type of DLBCL. Comparisons of the genome profiles of FL,both with and without BCL2 rearrangement, also revealed the existence of a unique subgroup: trisomy 3 FL. Comparison of genome profiles between acute type and lymphoma types of adult T cell lymphoma also demonstrated that acute and lymphoma types are genomically distinct subtypes, and thus may develop tumors via distinct genetic pathways. In addition to identifying disease-specific genomic alterations, we also discovered several target genes of the genomic gains and losses. Furthermore,we developed a computer algorithm to classify lymphoma diseases or subtypes on the basis of copy number gains and losses. We applied the algorithm to the classifications of DLBCL and MCL diseases and ABC and GCB subtypes. The method correctly classified the DLBCL and MCL diseases at 89%, and ABC and GCB subtypes at 83%. These results demonstrate that copy number gains and losses detected by array CGH could be used for classifying lymphomas into biologically and clinically distinct diseases or subtypes. The genomic copy number alterations detected by array CGH are therefore considered to have the potential to help diagnose or classify different disease entities and tumor subtypes.