Limits...
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.

Show MeSH

Related in: MedlinePlus

Gene fusions among the Hippo pathway genes in lung cancer. A, Schematic representation of core and associate members of the Hippo pathway adapted from Harvey et al29. Potential tumor suppressors are represented in green, while potential oncogenes are indicated in red. Phosphorylation of YAP or TAZ by LATS retains them in the cytoplasm and hinders their transcriptional regulation. B, Fusions in putative oncogenes of the Hippo pathway. C, Fusions in putative tumor suppressors of the Hippo pathway. For all fusion schematics represented, the wild-type Hippo pathway protein domain structure is presented first, numbers indicate total amino acids and domain names are abbreviated. Red arrows show the fusion junctions and red # symbol indicate protein truncation due to out-of-frame ORFs from fusion transcript analysis. The schematic of the previously reported TAZ-CAMTA1 fusion in epithelioid hemangioendothelioma (EH) 42 is also displayed. Protein abbreviations: MST1/2-STE20-like protein kinase; LATS1/2-Large Tumor Suppressor Homolog Kinase; YAP1-Yes-associated Protein 1; WWTR1-ww-Domain Containing Transcription Regulator 1; TEAD-TEA-Domain Family; HIPK2 Homeodomain Interacting Protein Kinase 2; TAOK1/3-TAO Kinase; FAT1-FAT Atypical Cadherin 1; DCHS2-Dachsous Cadherin-related 2; PTPN14-Protein Tyrosine Phosphatase, Non-receptor Type 14. Domain abbreviations: B4-Band 4.1 homologues; FERM_C-FERM C-terminal PH-like Domain; S_TKc-Serine/Threonine Protein Kinases, Catalytic Domain; PTPc-Protein Tyrosine Phosphatase, Catalytic Domain; CA-Cadherin Repeats; FIB-Fibrinogen; FBG-Fibrinogen-related Domains; WW-Domain with 2 conserved Trp (W) residues; TID-TEAD Interacting Domain; TAD-Transactivation Domain; ANK-Ankyrin Repeats; IQ-Short Calmodulin-binding Motif; EGF-Epidermal Growth Factor-like Domain; ZnFC2H2-Zinc Finger; TM-Transmembrane Domain.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4274748&req=5

Figure 3: Gene fusions among the Hippo pathway genes in lung cancer. A, Schematic representation of core and associate members of the Hippo pathway adapted from Harvey et al29. Potential tumor suppressors are represented in green, while potential oncogenes are indicated in red. Phosphorylation of YAP or TAZ by LATS retains them in the cytoplasm and hinders their transcriptional regulation. B, Fusions in putative oncogenes of the Hippo pathway. C, Fusions in putative tumor suppressors of the Hippo pathway. For all fusion schematics represented, the wild-type Hippo pathway protein domain structure is presented first, numbers indicate total amino acids and domain names are abbreviated. Red arrows show the fusion junctions and red # symbol indicate protein truncation due to out-of-frame ORFs from fusion transcript analysis. The schematic of the previously reported TAZ-CAMTA1 fusion in epithelioid hemangioendothelioma (EH) 42 is also displayed. Protein abbreviations: MST1/2-STE20-like protein kinase; LATS1/2-Large Tumor Suppressor Homolog Kinase; YAP1-Yes-associated Protein 1; WWTR1-ww-Domain Containing Transcription Regulator 1; TEAD-TEA-Domain Family; HIPK2 Homeodomain Interacting Protein Kinase 2; TAOK1/3-TAO Kinase; FAT1-FAT Atypical Cadherin 1; DCHS2-Dachsous Cadherin-related 2; PTPN14-Protein Tyrosine Phosphatase, Non-receptor Type 14. Domain abbreviations: B4-Band 4.1 homologues; FERM_C-FERM C-terminal PH-like Domain; S_TKc-Serine/Threonine Protein Kinases, Catalytic Domain; PTPc-Protein Tyrosine Phosphatase, Catalytic Domain; CA-Cadherin Repeats; FIB-Fibrinogen; FBG-Fibrinogen-related Domains; WW-Domain with 2 conserved Trp (W) residues; TID-TEAD Interacting Domain; TAD-Transactivation Domain; ANK-Ankyrin Repeats; IQ-Short Calmodulin-binding Motif; EGF-Epidermal Growth Factor-like Domain; ZnFC2H2-Zinc Finger; TM-Transmembrane Domain.

Mentions: The Hippo signaling pathway is highly conserved across species and plays a major role in cell polarity, cell-cell adhesion and contact inhibition29. The mammalian homologues of the Drosophila Hippo and Warts core serine threonine kinases are STE20-like protein kinase (MST1/2) and large tumor suppressor homolog kinase (LATS1/2) respectively. The core kinases regulate the activity and stability of the transcriptional co-activators yes-associated protein 1 (YAP1) and WW domain-containing transcription regulator 1 (WWTR1) through phosphorylation. Un-phosphorylated YAP/WWTR1 binds to TEA domain family (TEAD) transcription factors in the nucleus to regulate gene expression (Fig. 3A). Accessory members of the Hippo pathway such as KIBRA (WWC1), scribbled planar cell polarity (SCRIB) and Neurofibromin 2 (NF2) have been shown to activate the core kinases. An increasing number of studies have investigated the Hippo pathway in lung, colorectal, ovarian and liver cancers29. While animal model experiments support the Hippo pathway in tumorigenesis, no evidence for non-synonymous mutations in this pathway has been found in lung cancer. Few somatic or germ-line mutations discovered in Hippo pathway genes are found in common human cancers, with NF2 being the only gene known to be inactivated by mutation29. We observed novel recurrent NF2 fusions, where retention of only the first exon of NF2, in both NF2-OSBP2 and NF2-MORC2 fusions result in loss of function of this tumor suppressor gene (Fig. 3B and 3C) and several fusions involving core members of the Hippo pathway such as LATS1, YAP1, and WWTR1 (previously known as TAZ) (Fig. 3C). We also identified fusions in associate members of the Hippo pathway including, HIPK2, TAOK1, TAOK3, FAT1, DCHS2 and PTPN14 (Fig. 3B and 3C). Detailed inspection of the fusions revealed two intriguing aspects of these aberrations. Gene fusions in Hippo pathway tumor suppressor members such as LATS1, DCHS2, FAT1, TAOK1, TAOK3, PTPN14 and NF2 (Fig. 3B) abrogated their function by generating truncated proteins. However, fusions involving oncogenic proteins in the Hippo pathway such as WWTR1, YAP1 and HIPK2 retained their crucial functional domains Fig. 3B). Furthermore, we investigated the presence of additional genetic aberration in the index fusion samples and noticed that the vast majority lack known driver mutations (10 out of 14) (Supplementary Data 6). Using cbioportal (http://www.cbioportal.org) we discovered copy number loss and associated low mRNA expression of FAT1 in the index fusion sample (Supplementary Fig S6A) and copy gain and elevated expression of YAP1 in the sample harboring YAP1 fusion (Supplementary Fig S6B). These observations suggest that gene fusions are a novel mechanism of altering Hippo pathway genes potentially promoting a transforming phenotype. Taken together, the fusion landscape in lung cancer is highly heterogeneous and characterized by low recurrence and private fusions (Supplementary Data 5). Despite this heterogeneity, gene fusions could still be functionally relevant in lung cancers by affecting several members of common pathways such as those of the Hippo signaling cascade we observed here.


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)

Gene fusions among the Hippo pathway genes in lung cancer. A, Schematic representation of core and associate members of the Hippo pathway adapted from Harvey et al29. Potential tumor suppressors are represented in green, while potential oncogenes are indicated in red. Phosphorylation of YAP or TAZ by LATS retains them in the cytoplasm and hinders their transcriptional regulation. B, Fusions in putative oncogenes of the Hippo pathway. C, Fusions in putative tumor suppressors of the Hippo pathway. For all fusion schematics represented, the wild-type Hippo pathway protein domain structure is presented first, numbers indicate total amino acids and domain names are abbreviated. Red arrows show the fusion junctions and red # symbol indicate protein truncation due to out-of-frame ORFs from fusion transcript analysis. The schematic of the previously reported TAZ-CAMTA1 fusion in epithelioid hemangioendothelioma (EH) 42 is also displayed. Protein abbreviations: MST1/2-STE20-like protein kinase; LATS1/2-Large Tumor Suppressor Homolog Kinase; YAP1-Yes-associated Protein 1; WWTR1-ww-Domain Containing Transcription Regulator 1; TEAD-TEA-Domain Family; HIPK2 Homeodomain Interacting Protein Kinase 2; TAOK1/3-TAO Kinase; FAT1-FAT Atypical Cadherin 1; DCHS2-Dachsous Cadherin-related 2; PTPN14-Protein Tyrosine Phosphatase, Non-receptor Type 14. Domain abbreviations: B4-Band 4.1 homologues; FERM_C-FERM C-terminal PH-like Domain; S_TKc-Serine/Threonine Protein Kinases, Catalytic Domain; PTPc-Protein Tyrosine Phosphatase, Catalytic Domain; CA-Cadherin Repeats; FIB-Fibrinogen; FBG-Fibrinogen-related Domains; WW-Domain with 2 conserved Trp (W) residues; TID-TEAD Interacting Domain; TAD-Transactivation Domain; ANK-Ankyrin Repeats; IQ-Short Calmodulin-binding Motif; EGF-Epidermal Growth Factor-like Domain; ZnFC2H2-Zinc Finger; TM-Transmembrane Domain.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Gene fusions among the Hippo pathway genes in lung cancer. A, Schematic representation of core and associate members of the Hippo pathway adapted from Harvey et al29. Potential tumor suppressors are represented in green, while potential oncogenes are indicated in red. Phosphorylation of YAP or TAZ by LATS retains them in the cytoplasm and hinders their transcriptional regulation. B, Fusions in putative oncogenes of the Hippo pathway. C, Fusions in putative tumor suppressors of the Hippo pathway. For all fusion schematics represented, the wild-type Hippo pathway protein domain structure is presented first, numbers indicate total amino acids and domain names are abbreviated. Red arrows show the fusion junctions and red # symbol indicate protein truncation due to out-of-frame ORFs from fusion transcript analysis. The schematic of the previously reported TAZ-CAMTA1 fusion in epithelioid hemangioendothelioma (EH) 42 is also displayed. Protein abbreviations: MST1/2-STE20-like protein kinase; LATS1/2-Large Tumor Suppressor Homolog Kinase; YAP1-Yes-associated Protein 1; WWTR1-ww-Domain Containing Transcription Regulator 1; TEAD-TEA-Domain Family; HIPK2 Homeodomain Interacting Protein Kinase 2; TAOK1/3-TAO Kinase; FAT1-FAT Atypical Cadherin 1; DCHS2-Dachsous Cadherin-related 2; PTPN14-Protein Tyrosine Phosphatase, Non-receptor Type 14. Domain abbreviations: B4-Band 4.1 homologues; FERM_C-FERM C-terminal PH-like Domain; S_TKc-Serine/Threonine Protein Kinases, Catalytic Domain; PTPc-Protein Tyrosine Phosphatase, Catalytic Domain; CA-Cadherin Repeats; FIB-Fibrinogen; FBG-Fibrinogen-related Domains; WW-Domain with 2 conserved Trp (W) residues; TID-TEAD Interacting Domain; TAD-Transactivation Domain; ANK-Ankyrin Repeats; IQ-Short Calmodulin-binding Motif; EGF-Epidermal Growth Factor-like Domain; ZnFC2H2-Zinc Finger; TM-Transmembrane Domain.
Mentions: The Hippo signaling pathway is highly conserved across species and plays a major role in cell polarity, cell-cell adhesion and contact inhibition29. The mammalian homologues of the Drosophila Hippo and Warts core serine threonine kinases are STE20-like protein kinase (MST1/2) and large tumor suppressor homolog kinase (LATS1/2) respectively. The core kinases regulate the activity and stability of the transcriptional co-activators yes-associated protein 1 (YAP1) and WW domain-containing transcription regulator 1 (WWTR1) through phosphorylation. Un-phosphorylated YAP/WWTR1 binds to TEA domain family (TEAD) transcription factors in the nucleus to regulate gene expression (Fig. 3A). Accessory members of the Hippo pathway such as KIBRA (WWC1), scribbled planar cell polarity (SCRIB) and Neurofibromin 2 (NF2) have been shown to activate the core kinases. An increasing number of studies have investigated the Hippo pathway in lung, colorectal, ovarian and liver cancers29. While animal model experiments support the Hippo pathway in tumorigenesis, no evidence for non-synonymous mutations in this pathway has been found in lung cancer. Few somatic or germ-line mutations discovered in Hippo pathway genes are found in common human cancers, with NF2 being the only gene known to be inactivated by mutation29. We observed novel recurrent NF2 fusions, where retention of only the first exon of NF2, in both NF2-OSBP2 and NF2-MORC2 fusions result in loss of function of this tumor suppressor gene (Fig. 3B and 3C) and several fusions involving core members of the Hippo pathway such as LATS1, YAP1, and WWTR1 (previously known as TAZ) (Fig. 3C). We also identified fusions in associate members of the Hippo pathway including, HIPK2, TAOK1, TAOK3, FAT1, DCHS2 and PTPN14 (Fig. 3B and 3C). Detailed inspection of the fusions revealed two intriguing aspects of these aberrations. Gene fusions in Hippo pathway tumor suppressor members such as LATS1, DCHS2, FAT1, TAOK1, TAOK3, PTPN14 and NF2 (Fig. 3B) abrogated their function by generating truncated proteins. However, fusions involving oncogenic proteins in the Hippo pathway such as WWTR1, YAP1 and HIPK2 retained their crucial functional domains Fig. 3B). Furthermore, we investigated the presence of additional genetic aberration in the index fusion samples and noticed that the vast majority lack known driver mutations (10 out of 14) (Supplementary Data 6). Using cbioportal (http://www.cbioportal.org) we discovered copy number loss and associated low mRNA expression of FAT1 in the index fusion sample (Supplementary Fig S6A) and copy gain and elevated expression of YAP1 in the sample harboring YAP1 fusion (Supplementary Fig S6B). These observations suggest that gene fusions are a novel mechanism of altering Hippo pathway genes potentially promoting a transforming phenotype. Taken together, the fusion landscape in lung cancer is highly heterogeneous and characterized by low recurrence and private fusions (Supplementary Data 5). Despite this heterogeneity, gene fusions could still be functionally relevant in lung cancers by affecting several members of common pathways such as those of the Hippo signaling cascade we observed here.

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