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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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Recurrent activating MET exon skipping events. Right Panel: An activating MET exon-14 skipping event was observed in a total of 15 samples across all three cohorts. The total reads support each splice variant exon13–14 (blue), exon13–15(red) and exon14-15 (green) are represented in the bar plot on the right. In 5 out 11 TCGA samples where DNA mutation data was available, skipping of MET exon-14 was accompanied by a mutation affecting the splice donor site adjacent to position D1010 (illustrated inset on the right). Additionally one sample harbored a non-sense mutation g.chr7:116412024C>Gp.Y1003*, which accompanied exon-14 skipping. Left Panel: IGV browser view of splice site deletions/mutations in the corresponding samples.
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Figure 5: Recurrent activating MET exon skipping events. Right Panel: An activating MET exon-14 skipping event was observed in a total of 15 samples across all three cohorts. The total reads support each splice variant exon13–14 (blue), exon13–15(red) and exon14-15 (green) are represented in the bar plot on the right. In 5 out 11 TCGA samples where DNA mutation data was available, skipping of MET exon-14 was accompanied by a mutation affecting the splice donor site adjacent to position D1010 (illustrated inset on the right). Additionally one sample harbored a non-sense mutation g.chr7:116412024C>Gp.Y1003*, which accompanied exon-14 skipping. Left Panel: IGV browser view of splice site deletions/mutations in the corresponding samples.

Mentions: Recently, a significant percent of driver unknown lung cancer samples have been shown to harbor fusions involving ALK, ROS1, RET19, 23 kinases and an activating exon skipping in the c-MET oncogene23. Our analysis revealed that 1.3, 0.52 and 0.26 percent fusions involving ROS1, RET and ALK respectively among LUAD and LUSC with unknown driver. We detected c-MET exon-14 skipping in 15 samples, 14 of which occurred in driver unknown samples, a 3.6% (14/386) recurrence rate in this subpopulation (Fig. 5). Importantly, in 5 out 15 samples the skipping of c-MET exon-14 is likely caused by a mutation affecting the splice donor site adjacent to the amino acid position D1010 as previously described32. Our RNASeq data also validated the reported c-MET exon skipping event in the H596 cell line23.


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)

Recurrent activating MET exon skipping events. Right Panel: An activating MET exon-14 skipping event was observed in a total of 15 samples across all three cohorts. The total reads support each splice variant exon13–14 (blue), exon13–15(red) and exon14-15 (green) are represented in the bar plot on the right. In 5 out 11 TCGA samples where DNA mutation data was available, skipping of MET exon-14 was accompanied by a mutation affecting the splice donor site adjacent to position D1010 (illustrated inset on the right). Additionally one sample harbored a non-sense mutation g.chr7:116412024C>Gp.Y1003*, which accompanied exon-14 skipping. Left Panel: IGV browser view of splice site deletions/mutations in the corresponding samples.
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Related In: Results  -  Collection

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Figure 5: Recurrent activating MET exon skipping events. Right Panel: An activating MET exon-14 skipping event was observed in a total of 15 samples across all three cohorts. The total reads support each splice variant exon13–14 (blue), exon13–15(red) and exon14-15 (green) are represented in the bar plot on the right. In 5 out 11 TCGA samples where DNA mutation data was available, skipping of MET exon-14 was accompanied by a mutation affecting the splice donor site adjacent to position D1010 (illustrated inset on the right). Additionally one sample harbored a non-sense mutation g.chr7:116412024C>Gp.Y1003*, which accompanied exon-14 skipping. Left Panel: IGV browser view of splice site deletions/mutations in the corresponding samples.
Mentions: Recently, a significant percent of driver unknown lung cancer samples have been shown to harbor fusions involving ALK, ROS1, RET19, 23 kinases and an activating exon skipping in the c-MET oncogene23. Our analysis revealed that 1.3, 0.52 and 0.26 percent fusions involving ROS1, RET and ALK respectively among LUAD and LUSC with unknown driver. We detected c-MET exon-14 skipping in 15 samples, 14 of which occurred in driver unknown samples, a 3.6% (14/386) recurrence rate in this subpopulation (Fig. 5). Importantly, in 5 out 15 samples the skipping of c-MET exon-14 is likely caused by a mutation affecting the splice donor site adjacent to the amino acid position D1010 as previously described32. Our RNASeq data also validated the reported c-MET exon skipping event in the H596 cell line23.

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