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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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Gene fusion numbers correlates with lung cancer prognosis. A, Kaplan-Meier analysis for the combined cohort of lung cancer samples (n=594) with low (0–7) (n=124), intermediate (8–16) (n=237), or high (≥17) (n=233) number of fusions (Likelihood Ratio Test P=0.008). Samples with high number of fusions have worse prognosis (Cox survival analysis P=0.005). Individual Kaplan-Meier analyses with LUAD and LUSC samples are found in Supplementary Fig. 4A and 4B respectively.
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Figure 2: Gene fusion numbers correlates with lung cancer prognosis. A, Kaplan-Meier analysis for the combined cohort of lung cancer samples (n=594) with low (0–7) (n=124), intermediate (8–16) (n=237), or high (≥17) (n=233) number of fusions (Likelihood Ratio Test P=0.008). Samples with high number of fusions have worse prognosis (Cox survival analysis P=0.005). Individual Kaplan-Meier analyses with LUAD and LUSC samples are found in Supplementary Fig. 4A and 4B respectively.

Mentions: We investigated the relationship between the number of fusions present in a tumor and patient prognosis. Patients in our combined cohort were first classified into three fusion categories based on distribution percentiles as low (0–7), intermediate (8–17), or high (≥18) and then a 10-year Kaplan-Meier survival analysis was performed. Patients with high number of fusions had significantly shorter median overall survival (35.6, 95% confidence interval (CI) 27.2–43.9) compared to patients with intermediate (49.5, 95% CI 23.9–75.1) or low number of fusions (62.3, 95% CI 44.6–80.1; Likelihood ratio test P=0.008 Fig. 2). We observed similar results both for LUAD and LUSC when analyzed independently (Supplementary Fig. 4A and 4B). Statistically significant clinical covariates in the univariate Cox model (Supplementary Table 4) were used in the multivariate analysis to examine the prognostic value of fusion number. Strikingly, a high fusion incidence was independently associated with worse overall survival (HR=1.56, 95% CI 1.13–2.15, P=0.007, Supplementary Table 5) after adjusting for gender and disease stage. When TP53, KRAS and EGFR mutation status or smoking status was included in the multivariate analysis, the number of fusions remained independently associated with poor outcome (Supplementary Table 6).


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 fusion numbers correlates with lung cancer prognosis. A, Kaplan-Meier analysis for the combined cohort of lung cancer samples (n=594) with low (0–7) (n=124), intermediate (8–16) (n=237), or high (≥17) (n=233) number of fusions (Likelihood Ratio Test P=0.008). Samples with high number of fusions have worse prognosis (Cox survival analysis P=0.005). Individual Kaplan-Meier analyses with LUAD and LUSC samples are found in Supplementary Fig. 4A and 4B respectively.
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Related In: Results  -  Collection

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

Figure 2: Gene fusion numbers correlates with lung cancer prognosis. A, Kaplan-Meier analysis for the combined cohort of lung cancer samples (n=594) with low (0–7) (n=124), intermediate (8–16) (n=237), or high (≥17) (n=233) number of fusions (Likelihood Ratio Test P=0.008). Samples with high number of fusions have worse prognosis (Cox survival analysis P=0.005). Individual Kaplan-Meier analyses with LUAD and LUSC samples are found in Supplementary Fig. 4A and 4B respectively.
Mentions: We investigated the relationship between the number of fusions present in a tumor and patient prognosis. Patients in our combined cohort were first classified into three fusion categories based on distribution percentiles as low (0–7), intermediate (8–17), or high (≥18) and then a 10-year Kaplan-Meier survival analysis was performed. Patients with high number of fusions had significantly shorter median overall survival (35.6, 95% confidence interval (CI) 27.2–43.9) compared to patients with intermediate (49.5, 95% CI 23.9–75.1) or low number of fusions (62.3, 95% CI 44.6–80.1; Likelihood ratio test P=0.008 Fig. 2). We observed similar results both for LUAD and LUSC when analyzed independently (Supplementary Fig. 4A and 4B). Statistically significant clinical covariates in the univariate Cox model (Supplementary Table 4) were used in the multivariate analysis to examine the prognostic value of fusion number. Strikingly, a high fusion incidence was independently associated with worse overall survival (HR=1.56, 95% CI 1.13–2.15, P=0.007, Supplementary Table 5) after adjusting for gender and disease stage. When TP53, KRAS and EGFR mutation status or smoking status was included in the multivariate analysis, the number of fusions remained independently associated with poor outcome (Supplementary Table 6).

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