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Gene Signatures Stratify Computed Tomography Screening Detected Lung Cancer in High-Risk Populations.

Hu J, Boeri M, Sozzi G, Liu D, Marchianò A, Roz L, Pelosi G, Gatter K, Pastorino U, Pezzella F - EBioMedicine (2015)

Bottom Line: Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down-regulation of FOXO1A.Analysis of normal lung tissue from INT-IEO cohort produced signatures distinguishing patients with early from late detected tumours.The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.

ABSTRACT

Background: Although screening programmes of smokers have detected resectable early lung cancers more frequently than expected, their efficacy in reducing mortality remains debatable. To elucidate the biological features of computed tomography (CT) screening detected lung cancer, we examined the mRNA signatures on tumours according to the year of detection, stage and survival.

Methods: Gene expression profiles were analysed on 28 patients (INT-IEO training cohort) and 24 patients of Multicentre Italian Lung Detection (MILD validation cohort). The gene signatures generated from the training set were validated on the MILD set and a public deposited DNA microarray data set (GSE11969). Expression of selected genes and proteins was validated by real-time RT-PCR and immunohistochemistry. Enriched core pathway and pathway networks were explored by GeneSpring GX10.

Findings: A 239-gene signature was identified according to the year of tumour detection in the training INT-IEO set and correlated with the patients' outcomes. These signatures divided the MILD patients into two distinct survival groups independently of tumour stage, size, histopathological type and screening year. The signatures can also predict survival in the clinically detected cancers (GSE11969). Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down-regulation of FOXO1A. Analysis of normal lung tissue from INT-IEO cohort produced signatures distinguishing patients with early from late detected tumours.

Interpretation: The distinct pattern of "indolent" and "aggressive" tumour exists in CT-screening detected lung cancer according to the gene expression profiles. The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts.

No MeSH data available.


Related in: MedlinePlus

Pathway enrichment analysis reveals PI3K/PTEN/AKT signalling and apoptosis pathway as the most significantly related pathway. ITGB1 has higher level of expression in the late year tumours while FOXO1A has higher levels in the tumours detected at first two years.
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f0025: Pathway enrichment analysis reveals PI3K/PTEN/AKT signalling and apoptosis pathway as the most significantly related pathway. ITGB1 has higher level of expression in the late year tumours while FOXO1A has higher levels in the tumours detected at first two years.

Mentions: We performed network modelling using GeneSpring GX10 on the 239-gene signature of differentially expressed by CT1–2 vs CT3–5. The results showed that the tumours detected in later years have an increased expression of the genes ITGB1, SELP, PECAM1, F8, SERPINA3 with loss of FOXO1A as hub nodes in the transcriptome regulatory network (Fig. 4). Further pathway enrichment analysis (Table 6) revealed in functional terms that these data would predict the aggressive tumours form later years more angiogenesis (ITGB1) and metastases (ITGB1, PECAM1, SELP), increased proliferation and diminished apoptosis following loss of FOXP1 transcription but the activation of the of PI3K/PTEN/AKT pathway(Fig. 5).


Gene Signatures Stratify Computed Tomography Screening Detected Lung Cancer in High-Risk Populations.

Hu J, Boeri M, Sozzi G, Liu D, Marchianò A, Roz L, Pelosi G, Gatter K, Pastorino U, Pezzella F - EBioMedicine (2015)

Pathway enrichment analysis reveals PI3K/PTEN/AKT signalling and apoptosis pathway as the most significantly related pathway. ITGB1 has higher level of expression in the late year tumours while FOXO1A has higher levels in the tumours detected at first two years.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563137&req=5

f0025: Pathway enrichment analysis reveals PI3K/PTEN/AKT signalling and apoptosis pathway as the most significantly related pathway. ITGB1 has higher level of expression in the late year tumours while FOXO1A has higher levels in the tumours detected at first two years.
Mentions: We performed network modelling using GeneSpring GX10 on the 239-gene signature of differentially expressed by CT1–2 vs CT3–5. The results showed that the tumours detected in later years have an increased expression of the genes ITGB1, SELP, PECAM1, F8, SERPINA3 with loss of FOXO1A as hub nodes in the transcriptome regulatory network (Fig. 4). Further pathway enrichment analysis (Table 6) revealed in functional terms that these data would predict the aggressive tumours form later years more angiogenesis (ITGB1) and metastases (ITGB1, PECAM1, SELP), increased proliferation and diminished apoptosis following loss of FOXP1 transcription but the activation of the of PI3K/PTEN/AKT pathway(Fig. 5).

Bottom Line: Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down-regulation of FOXO1A.Analysis of normal lung tissue from INT-IEO cohort produced signatures distinguishing patients with early from late detected tumours.The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.

ABSTRACT

Background: Although screening programmes of smokers have detected resectable early lung cancers more frequently than expected, their efficacy in reducing mortality remains debatable. To elucidate the biological features of computed tomography (CT) screening detected lung cancer, we examined the mRNA signatures on tumours according to the year of detection, stage and survival.

Methods: Gene expression profiles were analysed on 28 patients (INT-IEO training cohort) and 24 patients of Multicentre Italian Lung Detection (MILD validation cohort). The gene signatures generated from the training set were validated on the MILD set and a public deposited DNA microarray data set (GSE11969). Expression of selected genes and proteins was validated by real-time RT-PCR and immunohistochemistry. Enriched core pathway and pathway networks were explored by GeneSpring GX10.

Findings: A 239-gene signature was identified according to the year of tumour detection in the training INT-IEO set and correlated with the patients' outcomes. These signatures divided the MILD patients into two distinct survival groups independently of tumour stage, size, histopathological type and screening year. The signatures can also predict survival in the clinically detected cancers (GSE11969). Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down-regulation of FOXO1A. Analysis of normal lung tissue from INT-IEO cohort produced signatures distinguishing patients with early from late detected tumours.

Interpretation: The distinct pattern of "indolent" and "aggressive" tumour exists in CT-screening detected lung cancer according to the gene expression profiles. The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts.

No MeSH data available.


Related in: MedlinePlus