The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.
BACKGROUND
The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival.


METHODS
Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index.


RESULTS
Three gene-expression subgroups--germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma--were identified. Two common oncogenic events in diffuse large-B-cell lymphoma, bcl-2 translocation and c-rel amplification, were detected only in the germinal-center B-cell-like subgroup. Patients in this subgroup had the highest five-year survival rate. To identify other molecular determinants of outcome, we searched for individual genes with expression patterns that correlated with survival in the preliminary group of patients. Most of these genes fell within four gene-expression signatures characteristic of germinal-center B cells, proliferating cells, reactive stromal and immune cells in the lymph node, or major-histocompatibility-complex class II complex. We used 17 genes to construct a predictor of overall survival after chemotherapy. This gene-based predictor and the international prognostic index were independent prognostic indicators.


CONCLUSIONS
DNA microarrays can be used to formulate a molecular predictor of survival after chemotherapy for diffuse large-B-cell lymphoma.
Rosenwald
Andreas
A
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md 20892, USA.
Wright
George
G
Chan
Wing C
WC
Connors
Joseph M
JM
Campo
Elias
E
Fisher
Richard I
RI
Gascoyne
Randy D
RD
Muller-Hermelink
H Konrad
HK
Smeland
Erlend B
EB
Giltnane
Jena M
JM
Hurt
Elaine M
EM
Zhao
Hong
H
Averett
Lauren
L
Yang
Liming
L
Wilson
Wyndham H
WH
Jaffe
Elaine S
ES
Simon
Richard
R
Klausner
Richard D
RD
Powell
John
J
Duffey
Patricia L
PL
Longo
Dan L
DL
Greiner
Timothy C
TC
Weisenburger
Dennis D
DD
Sanger
Warren G
WG
Dave
Bhavana J
BJ
Lynch
James C
JC
Vose
Julie
J
Armitage
James O
JO
Montserrat
Emilio
E
López-Guillermo
Armando
A
Grogan
Thomas M
TM
Miller
Thomas P
TP
LeBlanc
Michel
M
Ott
German
G
Kvaloy
Stein
S
Delabie
Jan
J
Holte
Harald
H
Krajci
Peter
P
Stokke
Trond
T
Staudt
Louis M
LM
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001706:Biopsy; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis
D000903:Antibiotics, Antineoplastic