A prognostic DNA methylation signature for stage I non-small-cell lung cancer

Juan Sandoval; Jesus Mendez-Gonzalez; Ernest Nadal; Guoan Chen; F Javier Carmona; Sergi Sayols; Sebastian Moran; Holger Heyn; Miguel Vizoso; Antonio Gomez; Montse Sanchez-Cespedes; Yassen Assenov; Fabian Müller; Christoph Bock; Miquel Taron; Josefina Mora; Lucia A Muscarella; Triantafillos Liloglou; Michael Davies; Marina Pollan; Maria J Pajares; Wenceslao Torre; Luis M Montuenga; Elisabeth Brambilla; John K Field; Luca Roz; Marco Lo Iacono; Giorgio V Scagliotti; Rafael Rosell; David G Beer; Manel Esteller

doi:10.1200/JCO.2012.48.5516

A prognostic DNA methylation signature for stage I non-small-cell lung cancer

Juan Sandoval, Jesus Mendez-Gonzalez, Ernest Nadal, Guoan Chen, F Javier Carmona, Sergi Sayols, Sebastian Moran, Holger Heyn, Miguel Vizoso, Antonio Gomez, Montse Sanchez-Cespedes, Yassen Assenov, Fabian Müller, Christoph Bock, Miquel Taron, Josefina Mora, Lucia A Muscarella, Triantafillos Liloglou, Michael Davies, Marina PollanMaria J Pajares, Wenceslao Torre, Luis M Montuenga, Elisabeth Brambilla, John K Field, Luca Roz, Marco Lo Iacono, Giorgio V Scagliotti, Rafael Rosell, David G Beer, Manel Esteller

Medical School

Research output: Contribution to journal › Article (journal) › peer-review

232 Citations (Scopus)

Abstract

PURPOSE: Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.

PATIENTS AND METHODS: A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.

RESULTS: Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).

CONCLUSION: The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.

Original language	English
Pages (from-to)	4140-7
Number of pages	8
Journal	Journal of Clinical Oncology
Volume	31
Issue number	32
DOIs	https://doi.org/10.1200/JCO.2012.48.5516
Publication status	Published - 10 Nov 2013

Keywords

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor/genetics
Carcinoma, Non-Small-Cell Lung/genetics
Cluster Analysis
CpG Islands/genetics
DNA Methylation/genetics
Disease-Free Survival
Female
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Lung Neoplasms/genetics
Male
Middle Aged
Neoplasm Staging
Oligonucleotide Array Sequence Analysis
Prognosis
Proportional Hazards Models
Transcriptome/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1200/JCO.2012.48.5516

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Sandoval, J., Mendez-Gonzalez, J., Nadal, E., Chen, G., Carmona, F. J., Sayols, S., Moran, S., Heyn, H., Vizoso, M., Gomez, A., Sanchez-Cespedes, M., Assenov, Y., Müller, F., Bock, C., Taron, M., Mora, J., Muscarella, L. A., Liloglou, T., Davies, M., ... Esteller, M. (2013). A prognostic DNA methylation signature for stage I non-small-cell lung cancer. Journal of Clinical Oncology, 31(32), 4140-7. https://doi.org/10.1200/JCO.2012.48.5516

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title = "A prognostic DNA methylation signature for stage I non-small-cell lung cancer",

abstract = "PURPOSE: Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.PATIENTS AND METHODS: A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.RESULTS: Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).CONCLUSION: The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.",

keywords = "Adult, Aged, Aged, 80 and over, Biomarkers, Tumor/genetics, Carcinoma, Non-Small-Cell Lung/genetics, Cluster Analysis, CpG Islands/genetics, DNA Methylation/genetics, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Lung Neoplasms/genetics, Male, Middle Aged, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Prognosis, Proportional Hazards Models, Transcriptome/genetics",

author = "Juan Sandoval and Jesus Mendez-Gonzalez and Ernest Nadal and Guoan Chen and Carmona, {F Javier} and Sergi Sayols and Sebastian Moran and Holger Heyn and Miguel Vizoso and Antonio Gomez and Montse Sanchez-Cespedes and Yassen Assenov and Fabian M{\"u}ller and Christoph Bock and Miquel Taron and Josefina Mora and Muscarella, {Lucia A} and Triantafillos Liloglou and Michael Davies and Marina Pollan and Pajares, {Maria J} and Wenceslao Torre and Montuenga, {Luis M} and Elisabeth Brambilla and Field, {John K} and Luca Roz and {Lo Iacono}, Marco and Scagliotti, {Giorgio V} and Rafael Rosell and Beer, {David G} and Manel Esteller",

year = "2013",

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day = "10",

doi = "10.1200/JCO.2012.48.5516",

language = "English",

volume = "31",

pages = "4140--7",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

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Sandoval, J, Mendez-Gonzalez, J, Nadal, E, Chen, G, Carmona, FJ, Sayols, S, Moran, S, Heyn, H, Vizoso, M, Gomez, A, Sanchez-Cespedes, M, Assenov, Y, Müller, F, Bock, C, Taron, M, Mora, J, Muscarella, LA, Liloglou, T, Davies, M, Pollan, M, Pajares, MJ, Torre, W, Montuenga, LM, Brambilla, E, Field, JK, Roz, L, Lo Iacono, M, Scagliotti, GV, Rosell, R, Beer, DG & Esteller, M 2013, 'A prognostic DNA methylation signature for stage I non-small-cell lung cancer', Journal of Clinical Oncology, vol. 31, no. 32, pp. 4140-7. https://doi.org/10.1200/JCO.2012.48.5516

TY - JOUR

T1 - A prognostic DNA methylation signature for stage I non-small-cell lung cancer

AU - Sandoval, Juan

AU - Mendez-Gonzalez, Jesus

AU - Nadal, Ernest

AU - Chen, Guoan

AU - Carmona, F Javier

AU - Sayols, Sergi

AU - Moran, Sebastian

AU - Heyn, Holger

AU - Vizoso, Miguel

AU - Gomez, Antonio

AU - Sanchez-Cespedes, Montse

AU - Assenov, Yassen

AU - Müller, Fabian

AU - Bock, Christoph

AU - Taron, Miquel

AU - Mora, Josefina

AU - Muscarella, Lucia A

AU - Liloglou, Triantafillos

AU - Davies, Michael

AU - Pollan, Marina

AU - Pajares, Maria J

AU - Torre, Wenceslao

AU - Montuenga, Luis M

AU - Brambilla, Elisabeth

AU - Field, John K

AU - Roz, Luca

AU - Lo Iacono, Marco

AU - Scagliotti, Giorgio V

AU - Rosell, Rafael

AU - Beer, David G

AU - Esteller, Manel

PY - 2013/11/10

Y1 - 2013/11/10

N2 - PURPOSE: Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.PATIENTS AND METHODS: A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.RESULTS: Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).CONCLUSION: The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.

AB - PURPOSE: Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard.PATIENTS AND METHODS: A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC.RESULTS: Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001).CONCLUSION: The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Biomarkers, Tumor/genetics

KW - Carcinoma, Non-Small-Cell Lung/genetics

KW - Cluster Analysis

KW - CpG Islands/genetics

KW - DNA Methylation/genetics

KW - Disease-Free Survival

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Kaplan-Meier Estimate

KW - Lung Neoplasms/genetics

KW - Male

KW - Middle Aged

KW - Neoplasm Staging

KW - Oligonucleotide Array Sequence Analysis

KW - Prognosis

KW - Proportional Hazards Models

KW - Transcriptome/genetics

U2 - 10.1200/JCO.2012.48.5516

DO - 10.1200/JCO.2012.48.5516

M3 - Article (journal)

C2 - 24081945

SN - 0732-183X

VL - 31

SP - 4140

EP - 4147

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 32

ER -

A prognostic DNA methylation signature for stage I non-small-cell lung cancer

Abstract

Keywords

UN SDGs

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