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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

Overall survival analysis of in silico data (GSE11969) considering (a) all the 79 patients or (b) the 40 stage I alone, grouped according to the signature of CT-year of screening. The (two-sided) p value is from by Log-rank (Mantel–Cox) test.
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f0015: Overall survival analysis of in silico data (GSE11969) considering (a) all the 79 patients or (b) the 40 stage I alone, grouped according to the signature of CT-year of screening. The (two-sided) p value is from by Log-rank (Mantel–Cox) test.

Mentions: We then tested the same signature on a deposited independent NSCLC data set with annotated clinical information (GSE11969) containing the expression profiles of 79 clinically detected lung adenocarcinomas and squamous cell carcinomas (Takeuchi et al., 2006). There were 118 features comparable with the dataset and able to divide the patients into two distinct survival groups independently from tumour stage and histotype (p = 0.013, Table 5). Moreover, the Kaplan–Meier curves showed clear differences in overall survival (Log-rank test p = 0.02) with 2.1 of HR (95%CI 1.1–3.9) as shown in Fig. 3a. When the analysis was restricted to 40 stage I tumours, the features also discriminated this early stage tumour with distinct clinical outcomes (p = 0.03 and HR = 2.9, 95%CI 1.1–7.8), suggesting that also clinically detected stage I tumours are a heterogeneous category comprising indolent and aggressive tumours (Fig. 3b). However, the stage generated signatures from the training set were ineffective in GSE11969 validation sets (Supplementary Table 15).


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)

Overall survival analysis of in silico data (GSE11969) considering (a) all the 79 patients or (b) the 40 stage I alone, grouped according to the signature of CT-year of screening. The (two-sided) p value is from by Log-rank (Mantel–Cox) test.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0015: Overall survival analysis of in silico data (GSE11969) considering (a) all the 79 patients or (b) the 40 stage I alone, grouped according to the signature of CT-year of screening. The (two-sided) p value is from by Log-rank (Mantel–Cox) test.
Mentions: We then tested the same signature on a deposited independent NSCLC data set with annotated clinical information (GSE11969) containing the expression profiles of 79 clinically detected lung adenocarcinomas and squamous cell carcinomas (Takeuchi et al., 2006). There were 118 features comparable with the dataset and able to divide the patients into two distinct survival groups independently from tumour stage and histotype (p = 0.013, Table 5). Moreover, the Kaplan–Meier curves showed clear differences in overall survival (Log-rank test p = 0.02) with 2.1 of HR (95%CI 1.1–3.9) as shown in Fig. 3a. When the analysis was restricted to 40 stage I tumours, the features also discriminated this early stage tumour with distinct clinical outcomes (p = 0.03 and HR = 2.9, 95%CI 1.1–7.8), suggesting that also clinically detected stage I tumours are a heterogeneous category comprising indolent and aggressive tumours (Fig. 3b). However, the stage generated signatures from the training set were ineffective in GSE11969 validation sets (Supplementary Table 15).

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