Integrated molecular portrait of non-small cell lung cancers

Vladimir Lazar; Chen Suo; Cedric Orear; Joost Van Den Oord; Zsofia Balogh; Justine Guegan; Bastien Job; Guillaume Meurice; Hugues Ripoche; Stefano Calza; Johanna Hasmats; Joakim Lundeberg; Ludovic Lacroix; Philippe Vielh; Fabienne Dufour; Janne Lehtiö; Rudolf Napieralski; Alexander Eggermont; Manfred Schmitt; Jacques Cadranel; Benjamin Besse; Philippe Girard; Fiona Blackhall; Pierre Validire; Jean Charles Soria; Philippe Dessen; Johan Hansson; Yudi Pawitan

doi:10.1186/1755-8794-6-53

Integrated molecular portrait of non-small cell lung cancers

Vladimir Lazar, Chen Suo, Cedric Orear, Joost Van Den Oord, Zsofia Balogh, Justine Guegan, Bastien Job, Guillaume Meurice, Hugues Ripoche, Stefano Calza, Johanna Hasmats, Joakim Lundeberg, Ludovic Lacroix, Philippe Vielh, Fabienne Dufour, Janne Lehtiö, Rudolf Napieralski, Alexander Eggermont, Manfred Schmitt, Jacques CadranelBenjamin Besse, Philippe Girard, Fiona Blackhall, Pierre Validire, Jean Charles Soria, Philippe Dessen, Johan Hansson, Yudi Pawitan

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

54 Citations (Scopus)

Abstract

Background: Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods. Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results: At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ∼800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions: Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.

Original language	English
Article number	53
Journal	BMC Medical Genomics
Volume	6
Issue number	1
DOIs	https://doi.org/10.1186/1755-8794-6-53
Publication status	Published - 3 Dec 2013

Keywords

AC
LCC
NSCLC
SCC
Systems biology

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10.1186/1755-8794-6-53

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Lazar, V., Suo, C., Orear, C., Van Den Oord, J., Balogh, Z., Guegan, J., Job, B., Meurice, G., Ripoche, H., Calza, S., Hasmats, J., Lundeberg, J., Lacroix, L., Vielh, P., Dufour, F., Lehtiö, J., Napieralski, R., Eggermont, A., Schmitt, M., ... Pawitan, Y. (2013). Integrated molecular portrait of non-small cell lung cancers. BMC Medical Genomics, 6(1), Article 53. https://doi.org/10.1186/1755-8794-6-53

@article{e30cc9b8ff0b43ad8a826b78f9d27220,

title = "Integrated molecular portrait of non-small cell lung cancers",

abstract = "Background: Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods. Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results: At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ∼800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions: Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.",

keywords = "AC, LCC, NSCLC, SCC, Systems biology",

author = "Vladimir Lazar and Chen Suo and Cedric Orear and {Van Den Oord}, Joost and Zsofia Balogh and Justine Guegan and Bastien Job and Guillaume Meurice and Hugues Ripoche and Stefano Calza and Johanna Hasmats and Joakim Lundeberg and Ludovic Lacroix and Philippe Vielh and Fabienne Dufour and Janne Lehti{\"o} and Rudolf Napieralski and Alexander Eggermont and Manfred Schmitt and Jacques Cadranel and Benjamin Besse and Philippe Girard and Fiona Blackhall and Pierre Validire and Soria, {Jean Charles} and Philippe Dessen and Johan Hansson and Yudi Pawitan",

year = "2013",

month = dec,

day = "3",

doi = "10.1186/1755-8794-6-53",

language = "English",

volume = "6",

journal = "BMC Medical Genomics",

issn = "1755-8794",

number = "1",

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Lazar, V, Suo, C, Orear, C, Van Den Oord, J, Balogh, Z, Guegan, J, Job, B, Meurice, G, Ripoche, H, Calza, S, Hasmats, J, Lundeberg, J, Lacroix, L, Vielh, P, Dufour, F, Lehtiö, J, Napieralski, R, Eggermont, A, Schmitt, M, Cadranel, J, Besse, B, Girard, P, Blackhall, F, Validire, P, Soria, JC, Dessen, P, Hansson, J & Pawitan, Y 2013, 'Integrated molecular portrait of non-small cell lung cancers', BMC Medical Genomics, vol. 6, no. 1, 53. https://doi.org/10.1186/1755-8794-6-53

TY - JOUR

T1 - Integrated molecular portrait of non-small cell lung cancers

AU - Lazar, Vladimir

AU - Suo, Chen

AU - Orear, Cedric

AU - Van Den Oord, Joost

AU - Balogh, Zsofia

AU - Guegan, Justine

AU - Job, Bastien

AU - Meurice, Guillaume

AU - Ripoche, Hugues

AU - Calza, Stefano

AU - Hasmats, Johanna

AU - Lundeberg, Joakim

AU - Lacroix, Ludovic

AU - Vielh, Philippe

AU - Dufour, Fabienne

AU - Lehtiö, Janne

AU - Napieralski, Rudolf

AU - Eggermont, Alexander

AU - Schmitt, Manfred

AU - Cadranel, Jacques

AU - Besse, Benjamin

AU - Girard, Philippe

AU - Blackhall, Fiona

AU - Validire, Pierre

AU - Soria, Jean Charles

AU - Dessen, Philippe

AU - Hansson, Johan

AU - Pawitan, Yudi

PY - 2013/12/3

Y1 - 2013/12/3

N2 - Background: Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods. Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results: At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ∼800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions: Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.

AB - Background: Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods. Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results: At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ∼800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions: Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.

KW - AC

KW - LCC

KW - NSCLC

KW - SCC

KW - Systems biology

UR - http://www.scopus.com/inward/record.url?scp=84888767796&partnerID=8YFLogxK

U2 - 10.1186/1755-8794-6-53

DO - 10.1186/1755-8794-6-53

M3 - Article

C2 - 24299561

AN - SCOPUS:84888767796

SN - 1755-8794

VL - 6

JO - BMC Medical Genomics

JF - BMC Medical Genomics

IS - 1

M1 - 53

ER -

Integrated molecular portrait of non-small cell lung cancers

Abstract

Keywords

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