Prediction of postoperative recurrence-free survival in non-small cell lung cancer by using an internationally validated gene expression model.
OBJECTIVE
This study was performed to discover prognostic genomic markers associated with postoperative outcome of stage I to III non-small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations.


METHODS
American patients (n = 27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n = 138) was also stratified by recurrence and screened for these genes. Four reproducible genes were identified and used to construct genomic and clinicogenomic Cox models for both cohorts.


RESULTS
Four genomic markers, DBN1 (drebrin 1), CACNB3 (calcium channel beta 3), FLAD1 (PP591; flavin adenine dinucleotide synthetase), and CCND2 (cyclin D2), exhibited highly significant differential expression in recurrent tumors in the training set (P < 0.001). In the validation set, DBN1, FLAD1 (PP591), and CACNB3 were significant by Cox univariate analysis (P ≤ 0.035), whereas only DBN1 was significant by multivariate analysis. Genomic and clinicogenomic models for recurrence-free survival (RFS) were equally effective for risk stratification of stage I to II or I to III patients (all models P < 0.0001). For stage I to II or I to III patients, 5-year RFS of the low- and high-risk patients was approximately 70% versus 30% for both models. The genomic model for overall survival of stage I to III patients was improved by addition of pT and pN stage (P < 0.0013 vs. 0.010).


CONCLUSIONS
A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I to III NSCLC patients.
Division of Hematology, Department of Medicine, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Ranjana
R
Mitra
Jinseon
J
Lee
Jisuk
J
Jo
Monica
M
Milani
Jeanette N
JN
McClintick
Howard J
HJ
Edenberg
Kenneth A
KA
Kesler
Karen M
KM
Rieger
Sunil
S
Badve
Oscar W
OW
Cummings
Ahmed
A
Mohiuddin
Dafydd G
DG
Thomas
Xianghua
X
Luo
Beth E
BE
Juliar
Lang
L
Li
Clementina
C
Mesaros
Ian A
IA
Blair
Anjaiah
A
Srirangam
Robert A
RA
Kratzke
Clement J
CJ
McDonald
Jhingook
J
Kim
David A
DA
Potter
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000592:standards; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D008957:Models, Genetic; D025202:Molecular Diagnostic Techniques / Q000592:standards; D009367:Neoplasm Staging; D011184:Postoperative Period; D011379:Prognosis; D012008:Recurrence; D012015:Reference Standards; D054928:Validation Studies as Topic
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