Combined clinical and genomic signatures for the prognosis of early stage non-small cell lung cancer based on gene copy number alterations

Aramburu, Ander; Zudaire, Isabel; Pajares, María J.; Agorreta, Jackeline; Orta, Alberto; Lozano, Marı́a D.; Gúrpide, Alfonso; Gómez-Román, Javier; Martínez-Climent, José A.; Jassem, Jacek; Skrzypski, Marcin; Suraokar, Milind; Behrens, Carmen; Wistuba, Ignacio I.; Pı́o, Rubén; Rubio, Ángel; Montuenga, Luis M.

doi:10.1186/s12864-015-1935-0

Cited by 13 publications

(14 citation statements)

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“…Previously, we showed the potential clinical relevance of gene amplification of YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) as part of a prognostic signature for patients with stage I or II lung adenocarcinoma (ADC) on the basis of copy number (CN) alterations and clinical profiles (4). YES1 is a nonreceptor cytoplasmic tyrosine kinase that belongs to the SRC family kinases (SFKs).…”

mentioning

confidence: 99%

YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib

Garmendia

Pajares

Hermida-Prado

et al. 2019

Am J Respir Crit Care Med

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Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.

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confidence: 99%

YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib

Garmendia

Pajares

Hermida-Prado

et al. 2019

Am J Respir Crit Care Med

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“…Next, we studied whether PGAM5 expression was correlated with the macrophage phenotype present in tumour tissue in NSCLC dataset GSE72194 [ 30 ]. There was a positive correlation of PGAM5 expression with one macrophage signature (‘module 49’) ( r = 0.3; p < 0.05) [Additional file 1 : Table S1].…”

Section: Resultsmentioning

confidence: 99%

“…Dataset GSE 31210 comprised of transcriptomic and outcome data for 226 primary Stage 1 and 2 lung adenocarcinomas [ 29 ]. Dataset GSE72194 [ 30 ] combined 5 previous datasets with the clinical and transcriptomic data of 338 adenocarcinomas and 294 squamous cell carcinomas.…”

Section: Methodsmentioning

confidence: 99%

PGAM5 expression and macrophage signatures in non-small cell lung cancer associated with chronic obstructive pulmonary disease (COPD)

et al. 2018

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BackgroundCOPD patients are at increased risk of developing non-small cell lung carcinoma that has a worse prognosis. Oxidative stress contributes to carcinogenesis and is increased in COPD patients due to mitochondrial dysfunction. We determined whether mitochondrial dysfunction is a contributing factor to the reduced survival of COPD patients with non-small cell lung carcinoma (NSCLC).MethodsUsing a transcriptomic database and outcome data of 3553 NSCLC samples, we selected mitochondrial-related genes whose levels in the tumour correlated with patient mortality. We further selected those genes showing a ≥ 2 fold expression in cancer compared to normal tissue. Cell-type specific expression of these proteins in lung tissue from NSCLC patients who were non-smokers or smokers with or without COPD (healthy smokers) was determined by immunohistochemistry. Gene set variation analysis was used in additional NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures within lung cancer tissue.ResultsThe expression of 14 mitochondrial-related genes was correlated with patient mortality and these were differentially expressed between cancer and normal lung tissue. We studied further the expression of one of these genes, PGAM5 which is a regulator of mitochondrial degradation by mitophagy. In background lung tissue, PGAM5 was only expressed in alveolar macrophages, with the highest expression in smokers with COPD compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer expressed PGAM5. Pre-neoplastic epithelium also showed the expression of PGAM5. There was no difference in expression in cancer tissue between COPD, healthy smoker and non-smoker groups. Macrophages at the edge of the cancer from COPD patients showed a trend towards higher expression of PGAM5 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and the level of expression of 9 out of 49 previously-defined macrophage transcriptomic signatures with a particular one associated with patient mortality (p < 0.05).ConclusionPGAM5 is expressed in pre-neoplastic tissue and NSCLC, but not in normal epithelium. The association between PGAM5 expression and patient mortality may be mediated through the induction of specific macrophage phenotypes.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5140-9) contains supplementary material, which is available to authorized users.

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“…Next, we studied whether PGAM5 or FUNDC1 expression was correlated with the macrophage phenotype in tumour tissue in NSCLC dataset GSE72194 [23]. The probe for FUNDC1 was not found in the transcriptomic data.…”

Section: Emphysema P Valuementioning

confidence: 99%

“…Dataset GSE 31210 comprised of transcriptomic and outcome data for 226 primary Stage 1 and 2 lung adenocarcinomas [22]. Dataset GSE72194 [23] combines 5 previous datasets with the clinical and transcriptomic data of 338 adenocarcinomas and 294 squamous cell carcinomas.…”

Section: Gene Set Variation Analysismentioning

confidence: 99%

Mitochondrial-Related Gene Expression and Macrophage Signatures in Non-Small Cell Lung Cancer, Including Patients with Emphysema as Co-Morbidity

F¹,

Ag²,

Pavlidis³

et al. 2017

J Clin Cell Immunol

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Objective: Our aim is to determine whether mitochondrial dysfunction is a contributing factor to the increased risk of non-small cell lung carcinoma (NSCLC) in COPD patients. Methods:The clinical relevance of mitochondrial-related gene expression in lung cancer was determined using transcriptomic data from more than 1000 human NSCLC samples. Immunohistochemistry was then used to study cell type specific expression of the relevant mitochondrial-related protein in normal and cancerous lung tissue. Gene set variation analysis (GSVA) was applied in NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures. Results:The expression of 33 mitochondrial-related genes was correlated with NSCLC patient survival. We studied further the expression of PGAM5 and FUNDC1, which are regulators of mitochondrial degradation (mitophagy). In background lung tissue, PGAM5 and FUNDC1 were only expressed in alveolar macrophages, with highest expression in smokers with emphysema compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer, expressed PGAM5 and FUNDC1. PGAM5 was also expressed in pre-neoplastic epithelium (squamous dysplasia and carcinoma in situ). There was no difference in expression in cancer tissue between the emphysema, healthy smokers and non-smokers group. Macrophages at the edge of the cancer from emphysema patients had a trend towards higher expression of PGAM5 and FUNDC1 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and 9 out of 49 previously defined macrophage transcriptomic signatures with one (module 22) associated with patient survival (p<0.05). Conclusion:PGAM5 is expressed in pre-neoplastic tissue and NSCLC, but not in normal epithelium. The association between PGAM5 expression and lung cancer outcome may be mediated by the induction of specific macrophage phenotypes.

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Combined clinical and genomic signatures for the prognosis of early stage non-small cell lung cancer based on gene copy number alterations

Cited by 13 publications

References 50 publications

YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib

YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to Dasatinib

PGAM5 expression and macrophage signatures in non-small cell lung cancer associated with chronic obstructive pulmonary disease (COPD)

Mitochondrial-Related Gene Expression and Macrophage Signatures in Non-Small Cell Lung Cancer, Including Patients with Emphysema as Co-Morbidity

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