An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup.
Effective treatment of diffuse large B-cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in a DLBCL cohort treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA sequencing data revealed novel deletions in RCOR1 to be associated with unfavorable progression-free survival (P = .001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (P = .023). The prognostic significance of the 233-gene signature for overall survival was reproduced in an independent cohort comprising 195 R-CHOP-treated patients (P = .039). Additionally, we discovered that within the International Prognostic Index low-risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. We present a novel and reproducible molecular subgroup of DLBCL that impacts risk-stratification of R-CHOP-treated DLBCL patients and reveals a possible new avenue for therapeutic intervention strategies.
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada;
Fong Chun
http://orcid.org/0000-0002-7825-2692
FC
Chan
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Adele
A
Telenius
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Shannon
S
Healy
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Susana
S
Ben-Neriah
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Anja
A
Mottok
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Raymond
http://orcid.org/0000-0001-8772-3882
R
Lim
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Marie
M
Drake
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Sandy
S
Hu
Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada;
Jiarui
http://orcid.org/0000-0003-3670-7764
J
Ding
Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada;
Gavin
G
Ha
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
David W
DW
Scott
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Robert
R
Kridel
Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada;
Ali
A
Bashashati
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Sanja
S
Rogic
Department of Oncology, McGill University, Montreal, QC, Canada;
Nathalie
N
Johnson
Genome Sciences Center, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
Ryan D
http://orcid.org/0000-0003-2932-7800
RD
Morin
Department of Pathology, University of Arizona, Tucson, AZ; and.
Lisa M
LM
Rimsza
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Laurie
L
Sehn
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Joseph M
http://orcid.org/0000-0002-1361-7531
JM
Connors
Genome Sciences Center, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Marco A
MA
Marra
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Randy D
RD
Gascoyne
Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada;
Sohrab P
SP
Shah
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
Christian
C
Steidl
D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000235:genetics*; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D000069283:Rituximab; D059467:Transcriptome; D014750:Vincristine / Q000627:therapeutic use
D058846:Antibodies, Monoclonal, Murine-Derived; D056970:Co-Repressor Proteins; D007155:Immunologic Factors; D009419:Nerve Tissue Proteins; C121019:RCOR1 protein, human; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone