TY - JOUR
T1 - Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients
AU - Lim, Emilia L.
AU - Trinh, Diane L.
AU - Scott, David W.
AU - Chu, Andy
AU - Krzywinski, Martin
AU - Zhao, Yongjun
AU - Robertson, A. Gordon
AU - Mungall, Andrew J.
AU - Schein, Jacqueline
AU - Boyle, Merrill
AU - Mottok, Anja
AU - Ennishi, Daisuke
AU - Johnson, Nathalie A.
AU - Steidl, Christian
AU - Connors, Joseph M.
AU - Morin, Ryan D.
AU - Gascoyne, Randy D.
AU - Marra, Marco A.
N1 - Funding Information:
The authors would like to thank the Library Construction, Biospecimen, Sequencing and Bioinformatics teams at Canada’s Michael Smith Genome Sciences Centre for expert technical assistance, Heather Kirk, Christina Macleod, Pawan Pandoh, and Helen McDonald for the preparation of the samples in the extended FFPET cohort; Suman Singh for assistance gathering and collating patient follow-up information; and all the patients, their families, and referring physicians of British Columbia for their support of this study. MAM acknowledges the support of the BC Cancer Agency, the BC Cancer Foundation, the Canada Foundation for Innovation, Genome BC, and Genome Canada. We are grateful for expert project management assistance provided by Dr. Karen Novik, Dr. Sherry Wang, Payal Sipahimalani, and Dr. Armelle Troussard. We would also like to thank Dr. Daniela Gerhard for valuable editorial comments. The results published here are in whole or part based upon data generated by The Cancer Genome Atlas managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov.
Funding Information:
ELL is supported by a Canadian Institutes of Health Research Doctoral Award and a University of British Columbia Four Year Fellowship. DWS is supported by a Postdoctoral Fellowship from the Canadian Institutes of Health Research. AM is supported by a Postdoctoral Fellowship Award from the Mildred-Scheel Cancer Foundation. CS is supported by a Career Investigator Award by the Michael Smith Foundation for Health research and is recipient of a Canadian Institutes of Health Research New Investigator award. JMC and RDG are supported in part by the BC Cancer Foundation and the Terry Fox Research Institute. MAM holds the University of British Columbia Canada Research Chair in Genome Science. The BC Cancer Agency Genome Sciences Centre and the BC Cancer Agency Centre for Lymphoid Cancer gratefully acknowledge funding support from John Auston, the BC Cancer Foundation, Genome Canada, Genome British Columbia, the Cancer Research Society and the Leukemia and Lymphoma Society of Canada. The research reported here was funded in part by The Terry Fox Foundation (grant 019001), Terry Fox Research Institute (grant #1023) and with Federal Funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. A full list of funders of infrastructure and research is available at www.bcgsc.ca/about/funding_support.
Publisher Copyright:
© 2015 Lim et al.; licensee BioMed Central.
PY - 2015/1/29
Y1 - 2015/1/29
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84937886780&partnerID=8YFLogxK
U2 - 10.1186/s13059-014-0568-y
DO - 10.1186/s13059-014-0568-y
M3 - Article
C2 - 25723320
AN - SCOPUS:84937886780
VL - 16
JO - Genome Biology
JF - Genome Biology
SN - 1474-7596
IS - 1
M1 - 18
ER -
