An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup

Fong Chun Chan, Adele Telenius, Shannon Healy, Susana Ben-Neriah, Anja Mottok, Raymond Lim, Marie Drake, Sandy Hu, Jiarui Ding, Gavin Ha, David W. Scott, Robert Kridel, Ali Bashashati, Sanja Rogic, Nathalie Johnson, Ryan D. Morin, Lisa M Rimsza, Laurie Sehn, Joseph M. Connors, Marco A. MarraRandy D. Gascoyne, Sohrab P. Shah, Christian Steidl

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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 sam-pleswith 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 cohortcomprising 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 patientsand reveals a possible new avenue for therapeutic intervention strategies.

Original languageEnglish (US)
Pages (from-to)959-966
Number of pages8
JournalBlood
Volume125
Issue number6
DOIs
StatePublished - Feb 5 2015

Fingerprint

Lymphoma, Large B-Cell, Diffuse
Transcriptome
Gene expression
Genes
Cells
Lymphoma
RNA Sequence Analysis
Survival
Vincristine
Prednisolone
Treatment Failure
Doxorubicin
Cyclophosphamide
Disease-Free Survival
Therapeutics
Genome
Phenotype
Cell Line
RNA

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

Chan, F. C., Telenius, A., Healy, S., Ben-Neriah, S., Mottok, A., Lim, R., ... Steidl, C. (2015). An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup. Blood, 125(6), 959-966. https://doi.org/10.1182/blood-2013-06-507152

An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup. / Chan, Fong Chun; Telenius, Adele; Healy, Shannon; Ben-Neriah, Susana; Mottok, Anja; Lim, Raymond; Drake, Marie; Hu, Sandy; Ding, Jiarui; Ha, Gavin; Scott, David W.; Kridel, Robert; Bashashati, Ali; Rogic, Sanja; Johnson, Nathalie; Morin, Ryan D.; Rimsza, Lisa M; Sehn, Laurie; Connors, Joseph M.; Marra, Marco A.; Gascoyne, Randy D.; Shah, Sohrab P.; Steidl, Christian.

In: Blood, Vol. 125, No. 6, 05.02.2015, p. 959-966.

Research output: Contribution to journalArticle

Chan, FC, Telenius, A, Healy, S, Ben-Neriah, S, Mottok, A, Lim, R, Drake, M, Hu, S, Ding, J, Ha, G, Scott, DW, Kridel, R, Bashashati, A, Rogic, S, Johnson, N, Morin, RD, Rimsza, LM, Sehn, L, Connors, JM, Marra, MA, Gascoyne, RD, Shah, SP & Steidl, C 2015, 'An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup', Blood, vol. 125, no. 6, pp. 959-966. https://doi.org/10.1182/blood-2013-06-507152
Chan, Fong Chun ; Telenius, Adele ; Healy, Shannon ; Ben-Neriah, Susana ; Mottok, Anja ; Lim, Raymond ; Drake, Marie ; Hu, Sandy ; Ding, Jiarui ; Ha, Gavin ; Scott, David W. ; Kridel, Robert ; Bashashati, Ali ; Rogic, Sanja ; Johnson, Nathalie ; Morin, Ryan D. ; Rimsza, Lisa M ; Sehn, Laurie ; Connors, Joseph M. ; Marra, Marco A. ; Gascoyne, Randy D. ; Shah, Sohrab P. ; Steidl, Christian. / An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup. In: Blood. 2015 ; Vol. 125, No. 6. pp. 959-966.
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AU - Chan, Fong Chun

AU - Telenius, Adele

AU - Healy, Shannon

AU - Ben-Neriah, Susana

AU - Mottok, Anja

AU - Lim, Raymond

AU - Drake, Marie

AU - Hu, Sandy

AU - Ding, Jiarui

AU - Ha, Gavin

AU - Scott, David W.

AU - Kridel, Robert

AU - Bashashati, Ali

AU - Rogic, Sanja

AU - Johnson, Nathalie

AU - Morin, Ryan D.

AU - Rimsza, Lisa M

AU - Sehn, Laurie

AU - Connors, Joseph M.

AU - Marra, Marco A.

AU - Gascoyne, Randy D.

AU - Shah, Sohrab P.

AU - Steidl, Christian

PY - 2015/2/5

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N2 - 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 sam-pleswith 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 cohortcomprising 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 patientsand reveals a possible new avenue for therapeutic intervention strategies.

AB - 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 sam-pleswith 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 cohortcomprising 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 patientsand reveals a possible new avenue for therapeutic intervention strategies.

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