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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

Unsupervised hierarchical clustering of 17 tumours detected in years 1 and 2 (T) and 11 cases detected in years 3, 4 and 5 (T*) using 239 differentially expressed genes.
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f0005: Unsupervised hierarchical clustering of 17 tumours detected in years 1 and 2 (T) and 11 cases detected in years 3, 4 and 5 (T*) using 239 differentially expressed genes.

Mentions: Unsupervised hierarchical clustering of the 239-gene showed the separation of CT1–2 and CT3–5 (Fig. 1). Similarly the method applied to 153 genes distinguished stage I from stages II–IV and 218 genes of CT1–2/stage I vs. CT years3–5/stage II–IV tumours respectively (Suppl. Fig. 1, Suppl. Fig. 2).


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)

Unsupervised hierarchical clustering of 17 tumours detected in years 1 and 2 (T) and 11 cases detected in years 3, 4 and 5 (T*) using 239 differentially expressed genes.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0005: Unsupervised hierarchical clustering of 17 tumours detected in years 1 and 2 (T) and 11 cases detected in years 3, 4 and 5 (T*) using 239 differentially expressed genes.
Mentions: Unsupervised hierarchical clustering of the 239-gene showed the separation of CT1–2 and CT3–5 (Fig. 1). Similarly the method applied to 153 genes distinguished stage I from stages II–IV and 218 genes of CT1–2/stage I vs. CT years3–5/stage II–IV tumours respectively (Suppl. Fig. 1, Suppl. Fig. 2).

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