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Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.

Dhanasekaran SM, Balbin OA, Chen G, Nadal E, Kalyana-Sundaram S, Pan J, Veeneman B, Cao X, Malik R, Vats P, Wang R, Huang S, Zhong J, Jing X, Iyer M, Wu YM, Harms PW, Lin J, Reddy R, Brennan C, Palanisamy N, Chang AC, Truini A, Truini M, Robinson DR, Beer DG, Chinnaiyan AM - Nat Commun (2014)

Bottom Line: Here we perform transcriptome analysis of 153 samples representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines.In addition, we observe exon-skipping events in c-MET, which are attributable to splice site mutations.These classes of genetic aberrations may play a significant role in the genesis of lung cancers lacking known driver mutations.

View Article: PubMed Central - PubMed

Affiliation: 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3].

ABSTRACT
Lung cancer is emerging as a paradigm for disease molecular subtyping, facilitating targeted therapy based on driving somatic alterations. Here we perform transcriptome analysis of 153 samples representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines. By integrating our data with The Cancer Genome Atlas and published sources, we analyse 753 lung cancer samples for gene fusions and other transcriptomic alterations. We show that higher numbers of gene fusions is an independent prognostic factor for poor survival in lung cancer. Our analysis confirms the recently reported CD74-NRG1 fusion and suggests that NRG1, NF1 and Hippo pathway fusions may play important roles in tumours without known driver mutations. In addition, we observe exon-skipping events in c-MET, which are attributable to splice site mutations. These classes of genetic aberrations may play a significant role in the genesis of lung cancers lacking known driver mutations.

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The gene fusion and mutational landscape of lung cancers. A, Lung adenocarcinoma (LUAD, n=451). B, Lung squamous carcinoma (LUSC, n=251). Top panels represent histograms depicting the number of high quality gene fusions identified in each sample. Central panels denote the presence or absence of activating mutations in known oncogenes (red), deleterious mutations in tumor suppressors (blue) no aberration (gray). Samples are represented in columns and genes in rows. Right middle panel are bar plot summarizing the number of samples harboring activating or deleterious mutations for each gene. Bottom panels indicate samples harboring both known and novel gene fusions (in green) involving either receptor kinase genes or NRG1. Samples in red indicate outlier expression pattern observed in the respective genes. Cohorts of additional non-small cell lung cancers including lung adenoid cystic carcinoma (ACC) (n=11) and large cell carcinomas (n=9) were also analyzed included in Supplementary Table 2.
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Figure 1: The gene fusion and mutational landscape of lung cancers. A, Lung adenocarcinoma (LUAD, n=451). B, Lung squamous carcinoma (LUSC, n=251). Top panels represent histograms depicting the number of high quality gene fusions identified in each sample. Central panels denote the presence or absence of activating mutations in known oncogenes (red), deleterious mutations in tumor suppressors (blue) no aberration (gray). Samples are represented in columns and genes in rows. Right middle panel are bar plot summarizing the number of samples harboring activating or deleterious mutations for each gene. Bottom panels indicate samples harboring both known and novel gene fusions (in green) involving either receptor kinase genes or NRG1. Samples in red indicate outlier expression pattern observed in the respective genes. Cohorts of additional non-small cell lung cancers including lung adenoid cystic carcinoma (ACC) (n=11) and large cell carcinomas (n=9) were also analyzed included in Supplementary Table 2.

Mentions: We developed the analysis pipeline, depicted in Supplementary Fig. 1 thus assessing gene fusions among all 753 patients in the combined cohort and for integration with mutation and clinical information (see Methods for details). For each sample we determined the mutation status of oncogenes and tumor suppressors known to play a role in lung cancer6 and reflected the previously reported mutational landscape of LUAD and LUSC (Fig. 1)4, 5, 7. KRAS was mutated in 30.1% and 1.6% of LUAD and LUSC respectively; EGFR in 13% and 1.6 of LUAD and LUSC; BRAF in 8% and 3.2% of LUAD and LUSC and PIK3CA in 7.6% and 13.5% of LUAD and LUSC respectively. As previously reported4, 5, 7, TP53 mutations are common in both LUAD and LUSC patients, 50.3% and 65.7% respectively (Fig. 1). The mutations identified among select genes in the characterized cell lines are summarized in Supplementary Fig. 2.


Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.

Dhanasekaran SM, Balbin OA, Chen G, Nadal E, Kalyana-Sundaram S, Pan J, Veeneman B, Cao X, Malik R, Vats P, Wang R, Huang S, Zhong J, Jing X, Iyer M, Wu YM, Harms PW, Lin J, Reddy R, Brennan C, Palanisamy N, Chang AC, Truini A, Truini M, Robinson DR, Beer DG, Chinnaiyan AM - Nat Commun (2014)

The gene fusion and mutational landscape of lung cancers. A, Lung adenocarcinoma (LUAD, n=451). B, Lung squamous carcinoma (LUSC, n=251). Top panels represent histograms depicting the number of high quality gene fusions identified in each sample. Central panels denote the presence or absence of activating mutations in known oncogenes (red), deleterious mutations in tumor suppressors (blue) no aberration (gray). Samples are represented in columns and genes in rows. Right middle panel are bar plot summarizing the number of samples harboring activating or deleterious mutations for each gene. Bottom panels indicate samples harboring both known and novel gene fusions (in green) involving either receptor kinase genes or NRG1. Samples in red indicate outlier expression pattern observed in the respective genes. Cohorts of additional non-small cell lung cancers including lung adenoid cystic carcinoma (ACC) (n=11) and large cell carcinomas (n=9) were also analyzed included in Supplementary Table 2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4274748&req=5

Figure 1: The gene fusion and mutational landscape of lung cancers. A, Lung adenocarcinoma (LUAD, n=451). B, Lung squamous carcinoma (LUSC, n=251). Top panels represent histograms depicting the number of high quality gene fusions identified in each sample. Central panels denote the presence or absence of activating mutations in known oncogenes (red), deleterious mutations in tumor suppressors (blue) no aberration (gray). Samples are represented in columns and genes in rows. Right middle panel are bar plot summarizing the number of samples harboring activating or deleterious mutations for each gene. Bottom panels indicate samples harboring both known and novel gene fusions (in green) involving either receptor kinase genes or NRG1. Samples in red indicate outlier expression pattern observed in the respective genes. Cohorts of additional non-small cell lung cancers including lung adenoid cystic carcinoma (ACC) (n=11) and large cell carcinomas (n=9) were also analyzed included in Supplementary Table 2.
Mentions: We developed the analysis pipeline, depicted in Supplementary Fig. 1 thus assessing gene fusions among all 753 patients in the combined cohort and for integration with mutation and clinical information (see Methods for details). For each sample we determined the mutation status of oncogenes and tumor suppressors known to play a role in lung cancer6 and reflected the previously reported mutational landscape of LUAD and LUSC (Fig. 1)4, 5, 7. KRAS was mutated in 30.1% and 1.6% of LUAD and LUSC respectively; EGFR in 13% and 1.6 of LUAD and LUSC; BRAF in 8% and 3.2% of LUAD and LUSC and PIK3CA in 7.6% and 13.5% of LUAD and LUSC respectively. As previously reported4, 5, 7, TP53 mutations are common in both LUAD and LUSC patients, 50.3% and 65.7% respectively (Fig. 1). The mutations identified among select genes in the characterized cell lines are summarized in Supplementary Fig. 2.

Bottom Line: Here we perform transcriptome analysis of 153 samples representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines.In addition, we observe exon-skipping events in c-MET, which are attributable to splice site mutations.These classes of genetic aberrations may play a significant role in the genesis of lung cancers lacking known driver mutations.

View Article: PubMed Central - PubMed

Affiliation: 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3].

ABSTRACT
Lung cancer is emerging as a paradigm for disease molecular subtyping, facilitating targeted therapy based on driving somatic alterations. Here we perform transcriptome analysis of 153 samples representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines. By integrating our data with The Cancer Genome Atlas and published sources, we analyse 753 lung cancer samples for gene fusions and other transcriptomic alterations. We show that higher numbers of gene fusions is an independent prognostic factor for poor survival in lung cancer. Our analysis confirms the recently reported CD74-NRG1 fusion and suggests that NRG1, NF1 and Hippo pathway fusions may play important roles in tumours without known driver mutations. In addition, we observe exon-skipping events in c-MET, which are attributable to splice site mutations. These classes of genetic aberrations may play a significant role in the genesis of lung cancers lacking known driver mutations.

Show MeSH
Related in: MedlinePlus