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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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Related in: MedlinePlus

Inactivating gene fusions of NF1 in lung cancer. A, NF1 protein schematic and the observed fusion breaks (red arrows) in the index cases are displayed on top. Recurrent NF1 fusions with partners (GOSR1, PSMD11, NLK, DRG2 and MYO15A antisense) resulted in loss of the NF1 gene as illustrated by the corresponding fusion protein structure below. Index samples are indicated in parenthesis and the numbers over the protein schematic indicate total amino acids. Red # symbol indicate protein truncation due to out-of-frame ORFs from fusion transcript analysis. B, UCSC browser view of genomic location of NF1 gene and its fusion partners (Top). Schematic representation of various NF1 rearrangements on chromosome 17 identified in lung cancer (Bottom).
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Figure 4: Inactivating gene fusions of NF1 in lung cancer. A, NF1 protein schematic and the observed fusion breaks (red arrows) in the index cases are displayed on top. Recurrent NF1 fusions with partners (GOSR1, PSMD11, NLK, DRG2 and MYO15A antisense) resulted in loss of the NF1 gene as illustrated by the corresponding fusion protein structure below. Index samples are indicated in parenthesis and the numbers over the protein schematic indicate total amino acids. Red # symbol indicate protein truncation due to out-of-frame ORFs from fusion transcript analysis. B, UCSC browser view of genomic location of NF1 gene and its fusion partners (Top). Schematic representation of various NF1 rearrangements on chromosome 17 identified in lung cancer (Bottom).

Mentions: Next, our integrative analysis combining fusion and mutation status revealed a total of 33 samples with aberrations in NF1 gene such as truncating fusions: GOSR1-NF1, NLK-NF1 and NF1-PSMD11 or deleterious mutations: non-sense, frame shift or splice site (Fig. 1, Fig. 4A and Supplementary Table 7). The fusions and mutations were observed in both LUAD and LUSC predominantly in driver negative samples (27 out of 33). Loss of NF1 promotes cell proliferation by de-repressing the mTOR pathway in a RAS-, PI3K-dependent fashion30, 31. The fusion architecture renders the tumor suppressor NF1 inactive by either truncating ORFs (GOSR1-NF1, NLK-NF1) or by destroying its functional domains (NF1-PSMD11), (Fig. 4A and 4B) indicating an alternate mechanism for NF1 inactivation in lung cancers besides somatic mutations4. To assess additional NF1 destructive fusions in lung cancer we did a comprehensive analysis assessing fusion junctions involving either exons or introns and found two additional events of NF1-DRG2_Antisense and NF1-MYO15A_Antisense present in the LS2 sample (Fig. 4A and 4B). The read evidence suggests genomic deletion as the mechanism for the NF1 fusions except in sample LS2 where centromeric inversion may be the underlying aberration (Fig. 4B). Importantly, 20 out 29 mutated NF1 samples and all NF1 truncating fusions were observed in samples without known drivers, accounting for 6.2% (24/386) of this subpopulation. Interestingly, two samples had fusions accompanying somatic mutations in NF1 potentially altering both the alleles of this tumor suppressor gene (Supplementary Table 7).


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)

Inactivating gene fusions of NF1 in lung cancer. A, NF1 protein schematic and the observed fusion breaks (red arrows) in the index cases are displayed on top. Recurrent NF1 fusions with partners (GOSR1, PSMD11, NLK, DRG2 and MYO15A antisense) resulted in loss of the NF1 gene as illustrated by the corresponding fusion protein structure below. Index samples are indicated in parenthesis and the numbers over the protein schematic indicate total amino acids. Red # symbol indicate protein truncation due to out-of-frame ORFs from fusion transcript analysis. B, UCSC browser view of genomic location of NF1 gene and its fusion partners (Top). Schematic representation of various NF1 rearrangements on chromosome 17 identified in lung cancer (Bottom).
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Figure 4: Inactivating gene fusions of NF1 in lung cancer. A, NF1 protein schematic and the observed fusion breaks (red arrows) in the index cases are displayed on top. Recurrent NF1 fusions with partners (GOSR1, PSMD11, NLK, DRG2 and MYO15A antisense) resulted in loss of the NF1 gene as illustrated by the corresponding fusion protein structure below. Index samples are indicated in parenthesis and the numbers over the protein schematic indicate total amino acids. Red # symbol indicate protein truncation due to out-of-frame ORFs from fusion transcript analysis. B, UCSC browser view of genomic location of NF1 gene and its fusion partners (Top). Schematic representation of various NF1 rearrangements on chromosome 17 identified in lung cancer (Bottom).
Mentions: Next, our integrative analysis combining fusion and mutation status revealed a total of 33 samples with aberrations in NF1 gene such as truncating fusions: GOSR1-NF1, NLK-NF1 and NF1-PSMD11 or deleterious mutations: non-sense, frame shift or splice site (Fig. 1, Fig. 4A and Supplementary Table 7). The fusions and mutations were observed in both LUAD and LUSC predominantly in driver negative samples (27 out of 33). Loss of NF1 promotes cell proliferation by de-repressing the mTOR pathway in a RAS-, PI3K-dependent fashion30, 31. The fusion architecture renders the tumor suppressor NF1 inactive by either truncating ORFs (GOSR1-NF1, NLK-NF1) or by destroying its functional domains (NF1-PSMD11), (Fig. 4A and 4B) indicating an alternate mechanism for NF1 inactivation in lung cancers besides somatic mutations4. To assess additional NF1 destructive fusions in lung cancer we did a comprehensive analysis assessing fusion junctions involving either exons or introns and found two additional events of NF1-DRG2_Antisense and NF1-MYO15A_Antisense present in the LS2 sample (Fig. 4A and 4B). The read evidence suggests genomic deletion as the mechanism for the NF1 fusions except in sample LS2 where centromeric inversion may be the underlying aberration (Fig. 4B). Importantly, 20 out 29 mutated NF1 samples and all NF1 truncating fusions were observed in samples without known drivers, accounting for 6.2% (24/386) of this subpopulation. Interestingly, two samples had fusions accompanying somatic mutations in NF1 potentially altering both the alleles of this tumor suppressor gene (Supplementary Table 7).

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