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Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients.

Lim EL, Trinh DL, Scott DW, Chu A, Krzywinski M, Zhao Y, Robertson AG, Mungall AJ, Schein J, Boyle M, Mottok A, Ennishi D, Johnson NA, Steidl C, Connors JM, Morin RD, Gascoyne RD, Marra MA - Genome Biol. (2015)

Bottom Line: Of these 25 miRNAs, six miRNAs are significantly associated with survival in our validation cohort.Abundant expression of miR-28-5p, miR-214-5p, miR-339-3p, and miR-5586-5p is associated with superior outcome, while abundant expression of miR-324-5p and NOVELM00203M is associated with inferior outcome.Our comprehensive sequence analysis of the DLBCL miRNome identifies candidate novel miRNAs and miRNAs associated with survival, reinforces results from previous mutational analyses, and reveals regulatory networks of significance for lymphomagenesis.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, with 30% to 40% of patients failing to be cured with available primary therapy. microRNAs (miRNAs) are RNA molecules that attenuate expression of their mRNA targets. To characterize the DLBCL miRNome, we sequenced miRNAs from 92 DLBCL and 15 benign centroblast fresh frozen samples and from 140 DLBCL formalin-fixed, paraffin-embedded tissue samples for validation.

Results: We identify known and candidate novel miRNAs, 25 of which are associated with survival independently of cell-of-origin and International Prognostic Index scores, which are established indicators of outcome. Of these 25 miRNAs, six miRNAs are significantly associated with survival in our validation cohort. Abundant expression of miR-28-5p, miR-214-5p, miR-339-3p, and miR-5586-5p is associated with superior outcome, while abundant expression of miR-324-5p and NOVELM00203M is associated with inferior outcome. Comparison of DLBCL miRNA-seq expression profiles with those from other cancer types identifies miRNAs that were more abundant in B-cell contexts. Unsupervised clustering of miRNAs identifies two clusters of patients that have distinct differences in their outcomes. Our integrative miRNA and mRNA expression analyses reveal that miRNAs increased in abundance in DLBCL appear to regulate the expression of genes involved in metabolism, cell cycle, and protein modification. Additionally, these miRNAs, including one candidate novel miRNA, miR-10393-3p, appear to target chromatin modification genes that are frequent targets of somatic mutation in non-Hodgkin lymphomas.

Conclusions: Our comprehensive sequence analysis of the DLBCL miRNome identifies candidate novel miRNAs and miRNAs associated with survival, reinforces results from previous mutational analyses, and reveals regulatory networks of significance for lymphomagenesis.

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Candidate miRNA:mRNA interactions in DLBCL. Chart showing Gene Ontology (GO) Biological Process terms that were enriched for genes involved in reciprocally expressed miRNA:mRNA pairs. Each column indicates a miRNA that is either increased or decreased in abundance in comparisons between DLBCL and centroblasts. Each row represents a GO term. A grey bar indicates that the GO term is significantly enriched in the candidate gene targets of one or more miRNA. Only GO Terms that have been enriched by targets of at least two miRNAs are shown. The number of miRNAs in each category are shown on the right.
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Fig3: Candidate miRNA:mRNA interactions in DLBCL. Chart showing Gene Ontology (GO) Biological Process terms that were enriched for genes involved in reciprocally expressed miRNA:mRNA pairs. Each column indicates a miRNA that is either increased or decreased in abundance in comparisons between DLBCL and centroblasts. Each row represents a GO term. A grey bar indicates that the GO term is significantly enriched in the candidate gene targets of one or more miRNA. Only GO Terms that have been enriched by targets of at least two miRNAs are shown. The number of miRNAs in each category are shown on the right.

Mentions: miRNA expression can regulate translation and mRNA stability. Considering the latter mechanism, we assessed the relationship between aberrantly expressed miRNA and mRNA abundance. Using the miRNA and mRNA profiles from the 92 DLBCL and 15 centroblast samples, we identified putative miRNA:mRNA regulatory interactions (Additional file 9: Figure S2; Additional file 5: Table S5). miRNAs that were more abundantly expressed in DLBCL appeared to interact with genes enriched in the Gene Ontology (GO) biological processes related to cell cycle, metabolic processes, chromatin modification, protein modification, nerve growth factor signaling pathways, and organelle organization (Figure 3, Additional file 10: Table S9). Conversely, miRNAs that were expressed at lower levels in DLBCL appeared to interact with genes that were enriched in GO biological processes related to extracellular organization, cellular adhesion, defense and wounding responses, actin cytoskeleton organization, blood vessel morphogenesis, and endocytosis (Figure 3, Additional file 10: Table S9).Figure 3


Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients.

Lim EL, Trinh DL, Scott DW, Chu A, Krzywinski M, Zhao Y, Robertson AG, Mungall AJ, Schein J, Boyle M, Mottok A, Ennishi D, Johnson NA, Steidl C, Connors JM, Morin RD, Gascoyne RD, Marra MA - Genome Biol. (2015)

Candidate miRNA:mRNA interactions in DLBCL. Chart showing Gene Ontology (GO) Biological Process terms that were enriched for genes involved in reciprocally expressed miRNA:mRNA pairs. Each column indicates a miRNA that is either increased or decreased in abundance in comparisons between DLBCL and centroblasts. Each row represents a GO term. A grey bar indicates that the GO term is significantly enriched in the candidate gene targets of one or more miRNA. Only GO Terms that have been enriched by targets of at least two miRNAs are shown. The number of miRNAs in each category are shown on the right.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308918&req=5

Fig3: Candidate miRNA:mRNA interactions in DLBCL. Chart showing Gene Ontology (GO) Biological Process terms that were enriched for genes involved in reciprocally expressed miRNA:mRNA pairs. Each column indicates a miRNA that is either increased or decreased in abundance in comparisons between DLBCL and centroblasts. Each row represents a GO term. A grey bar indicates that the GO term is significantly enriched in the candidate gene targets of one or more miRNA. Only GO Terms that have been enriched by targets of at least two miRNAs are shown. The number of miRNAs in each category are shown on the right.
Mentions: miRNA expression can regulate translation and mRNA stability. Considering the latter mechanism, we assessed the relationship between aberrantly expressed miRNA and mRNA abundance. Using the miRNA and mRNA profiles from the 92 DLBCL and 15 centroblast samples, we identified putative miRNA:mRNA regulatory interactions (Additional file 9: Figure S2; Additional file 5: Table S5). miRNAs that were more abundantly expressed in DLBCL appeared to interact with genes enriched in the Gene Ontology (GO) biological processes related to cell cycle, metabolic processes, chromatin modification, protein modification, nerve growth factor signaling pathways, and organelle organization (Figure 3, Additional file 10: Table S9). Conversely, miRNAs that were expressed at lower levels in DLBCL appeared to interact with genes that were enriched in GO biological processes related to extracellular organization, cellular adhesion, defense and wounding responses, actin cytoskeleton organization, blood vessel morphogenesis, and endocytosis (Figure 3, Additional file 10: Table S9).Figure 3

Bottom Line: Of these 25 miRNAs, six miRNAs are significantly associated with survival in our validation cohort.Abundant expression of miR-28-5p, miR-214-5p, miR-339-3p, and miR-5586-5p is associated with superior outcome, while abundant expression of miR-324-5p and NOVELM00203M is associated with inferior outcome.Our comprehensive sequence analysis of the DLBCL miRNome identifies candidate novel miRNAs and miRNAs associated with survival, reinforces results from previous mutational analyses, and reveals regulatory networks of significance for lymphomagenesis.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, with 30% to 40% of patients failing to be cured with available primary therapy. microRNAs (miRNAs) are RNA molecules that attenuate expression of their mRNA targets. To characterize the DLBCL miRNome, we sequenced miRNAs from 92 DLBCL and 15 benign centroblast fresh frozen samples and from 140 DLBCL formalin-fixed, paraffin-embedded tissue samples for validation.

Results: We identify known and candidate novel miRNAs, 25 of which are associated with survival independently of cell-of-origin and International Prognostic Index scores, which are established indicators of outcome. Of these 25 miRNAs, six miRNAs are significantly associated with survival in our validation cohort. Abundant expression of miR-28-5p, miR-214-5p, miR-339-3p, and miR-5586-5p is associated with superior outcome, while abundant expression of miR-324-5p and NOVELM00203M is associated with inferior outcome. Comparison of DLBCL miRNA-seq expression profiles with those from other cancer types identifies miRNAs that were more abundant in B-cell contexts. Unsupervised clustering of miRNAs identifies two clusters of patients that have distinct differences in their outcomes. Our integrative miRNA and mRNA expression analyses reveal that miRNAs increased in abundance in DLBCL appear to regulate the expression of genes involved in metabolism, cell cycle, and protein modification. Additionally, these miRNAs, including one candidate novel miRNA, miR-10393-3p, appear to target chromatin modification genes that are frequent targets of somatic mutation in non-Hodgkin lymphomas.

Conclusions: Our comprehensive sequence analysis of the DLBCL miRNome identifies candidate novel miRNAs and miRNAs associated with survival, reinforces results from previous mutational analyses, and reveals regulatory networks of significance for lymphomagenesis.

Show MeSH
Related in: MedlinePlus