Gene expression signature-based prognostic risk score in patients with primary central nervous system lymphoma.
OBJECTIVE
Better understanding of the underlying biology of primary central nervous system lymphomas (PCNSL) is critical for the development of early detection strategies, molecular markers, and new therapeutics. This study aimed to define genes associated with survival of patients with PCNSL.


METHODS
Expression profiling was conducted on 32 PCNSLs. A gene classifier was developed using the random survival forests model. On the basis of this, prognosis prediction score (PPS) using immunohistochemical analysis is also developed and validated in another data set with 43 PCNSLs.


RESULTS
We identified 23 genes in which expressions were strongly and consistently related to patient survival. A PPS was developed for overall survival (OS) using a univariate Cox model. Survival analyses using the selected 23-gene classifiers revealed a prognostic value for high-dose methotrexate (HD-MTX) and HD-MTX-containing polychemotherapy regimen-treated patients. Patients predicted to have good outcomes by the PPS showed significantly longer survival than those with poor predicted outcomes (P < 0.0001). PPS using immunohistochemical analysis is also significant in test (P = 0.0004) and validation data set (P = 0.0281). The gene-based predictor was an independent prognostic factor in a multivariate model that included clinical risk stratification (P < 0.0001). Among the genes, BRCA1 protein expressions were most strongly associated with patient survival.


CONCLUSIONS
We have identified gene expression signatures that can accurately predict survival in patients with PCNSL. These predictive genes should be useful as molecular biomarkers and they could provide novel targets for therapeutic interventions.
Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan.
Atsushi
A
Kawaguchi
Yasuo
Y
Iwadate
Yoshihiro
Y
Komohara
Masakazu
M
Sano
Koji
K
Kajiwara
Naoki
N
Yajima
Naoto
N
Tsuchiya
Jumpei
J
Homma
Hiroshi
H
Aoki
Tsutomu
T
Kobayashi
Yuko
Y
Sakai
Hiroaki
H
Hondoh
Yukihiko
Y
Fujii
Tatsuyuki
T
Kakuma
Ryuya
R
Yamanaka
D000368:Aged; D019313:BRCA1 Protein / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D012307:Risk Factors; D059467:Transcriptome
D019313:BRCA1 Protein; C492913:BRCA1 protein, human