Copy number abnormalities, MYC activity, and the genetic fingerprint of normal B cells mechanistically define the microRNA profile of diffuse large B-cell lymphoma.
MicroRNA (miRNA) deregulation contributes to cancer pathogenesis. However, analysis of miRNAs in diffuse large B-cell lymphoma (DLBCL) has been hindered by a focus on cell lines, limited number of miRNAs examined, and lack of copy number data. To address these restrictions, we investigated genomewide miRNA expression and copy number data in 86 DLBCLs. Permutation analysis showed that 63 miRNAs were recurrently disrupted in DLBCL, including highly expressed oncomirs not previously linked to chromosomal abnormalities. Further, using training and validation tumor groups, we defined a collection of miRNAs that robustly segregates DLBCLs into 3 subsets, which are independent of the cell-of-origin classification, extent of T-cell infiltrate, and tumor site. Instead, these unique miRNA-driven DLBCL subgroups showed markedly different MYC transcriptional activity, which explained the dominance of miRNAs regulated by MYC in their expression signatures. In addition, analysis of miRNA expression patterns of normal B cells and integration of copy number and expression data showed that genomic abnormalities and the genetic fingerprint of nonmalignant cells also contribute to the miRNA profile of DLBCL. In conclusion, we created a comprehensive map of the miRNA genome in DLBCL and, in the process, have uncovered and mechanistically elucidated the basis for additional molecular heterogeneity in this tumor.
Li
Cheng
C
Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
Kim
Sang-Woo
SW
Rai
Deepak
D
Bolla
Aswani R
AR
Adhvaryu
Siddharth
S
Kinney
Marsha C
MC
Robetorye
Ryan S
RS
Aguiar
Ricardo C T
RC
D001402:B-Lymphocytes / Q000378:metabolism*; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D018740:Genetic Heterogeneity; D055106:Genome-Wide Association Study; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic
D035683:MicroRNAs; D012334:RNA, Neoplasm