Prediction of postoperative recurrence-free survival in non-small cell lung cancer by using an internationally validated gene expression model

Ranjana Mitra, Jinseon Lee, Jisuk Jo, Monica Milani, Jeanette McClintick, Howard Edenberg, Kenneth Kesler, Karen Rieger, Sunil Badve, Oscar Cummings, Ahmed Mohiuddin, Dafydd G. Thomas, Xianghua Luo, Beth E. Juliar, Lang Li, Clementina Mesaros, Ian A. Blair, Anjaiah Srirangam, Robert A. Kratzke, Clement J. McDonaldJhingook Kim, David A. Potter

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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). Conclusion: A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I to III NSCLC patients.

Original languageEnglish
Pages (from-to)2934-2946
Number of pages13
JournalClinical Cancer Research
Volume17
Issue number9
DOIs
StatePublished - May 1 2011

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Non-Small Cell Lung Carcinoma
Gene Expression
Recurrence
Survival
Calcium Channels
Genes
Cyclin D2
Flavin-Adenine Dinucleotide
Ligases
Proportional Hazards Models
Neoplasms
Research Design
Multivariate Analysis
drebrins
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Prediction of postoperative recurrence-free survival in non-small cell lung cancer by using an internationally validated gene expression model. / Mitra, Ranjana; Lee, Jinseon; Jo, Jisuk; Milani, Monica; McClintick, Jeanette; Edenberg, Howard; Kesler, Kenneth; Rieger, Karen; Badve, Sunil; Cummings, Oscar; Mohiuddin, Ahmed; Thomas, Dafydd G.; Luo, Xianghua; Juliar, Beth E.; Li, Lang; Mesaros, Clementina; Blair, Ian A.; Srirangam, Anjaiah; Kratzke, Robert A.; McDonald, Clement J.; Kim, Jhingook; Potter, David A.

In: Clinical Cancer Research, Vol. 17, No. 9, 01.05.2011, p. 2934-2946.

Research output: Contribution to journalArticle

Mitra, R, Lee, J, Jo, J, Milani, M, McClintick, J, Edenberg, H, Kesler, K, Rieger, K, Badve, S, Cummings, O, Mohiuddin, A, Thomas, DG, Luo, X, Juliar, BE, Li, L, Mesaros, C, Blair, IA, Srirangam, A, Kratzke, RA, McDonald, CJ, Kim, J & Potter, DA 2011, 'Prediction of postoperative recurrence-free survival in non-small cell lung cancer by using an internationally validated gene expression model', Clinical Cancer Research, vol. 17, no. 9, pp. 2934-2946. https://doi.org/10.1158/1078-0432.CCR-10-1803
Mitra, Ranjana ; Lee, Jinseon ; Jo, Jisuk ; Milani, Monica ; McClintick, Jeanette ; Edenberg, Howard ; Kesler, Kenneth ; Rieger, Karen ; Badve, Sunil ; Cummings, Oscar ; Mohiuddin, Ahmed ; Thomas, Dafydd G. ; Luo, Xianghua ; Juliar, Beth E. ; Li, Lang ; Mesaros, Clementina ; Blair, Ian A. ; Srirangam, Anjaiah ; Kratzke, Robert A. ; McDonald, Clement J. ; Kim, Jhingook ; Potter, David A. / Prediction of postoperative recurrence-free survival in non-small cell lung cancer by using an internationally validated gene expression model. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 9. pp. 2934-2946.
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AU - Mitra, Ranjana

AU - Lee, Jinseon

AU - Jo, Jisuk

AU - Milani, Monica

AU - McClintick, Jeanette

AU - Edenberg, Howard

AU - Kesler, Kenneth

AU - Rieger, Karen

AU - Badve, Sunil

AU - Cummings, Oscar

AU - Mohiuddin, Ahmed

AU - Thomas, Dafydd G.

AU - Luo, Xianghua

AU - Juliar, Beth E.

AU - Li, Lang

AU - Mesaros, Clementina

AU - Blair, Ian A.

AU - Srirangam, Anjaiah

AU - Kratzke, Robert A.

AU - McDonald, Clement J.

AU - Kim, Jhingook

AU - Potter, David A.

PY - 2011/5/1

Y1 - 2011/5/1

N2 - Purpose: 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. Experimental Design: 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). Conclusion: A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I to III NSCLC patients.

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