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Transcriptome profiles of carcinoma-in-situ and invasive non-small cell lung cancer as revealed by SAGE.

Lonergan KM, Chari R, Coe BP, Wilson IM, Tsao MS, Ng RT, Macaulay C, Lam S, Lam WL - PLoS ONE (2010)

Bottom Line: Expression of genes associated with epidermal development, and loss of expression of genes associated with mucociliary biology, are predominant features of CIS, largely shared with precancerous lesions.Additionally, expression of genes associated with xenobiotic metabolism/detoxification is a notable feature of CIS, and is largely maintained in invasive cancer.Additionally, up-regulated genes detected at extreme differences between CIS and invasive cancer may have potential to serve as biomarkers for early detection.

View Article: PubMed Central - PubMed

Affiliation: Genetics Unit, Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.

ABSTRACT

Background: Non-small cell lung cancer (NSCLC) presents as a progressive disease spanning precancerous, preinvasive, locally invasive, and metastatic lesions. Identification of biological pathways reflective of these progressive stages, and aberrantly expressed genes associated with these pathways, would conceivably enhance therapeutic approaches to this devastating disease.

Methodology/principal findings: Through the construction and analysis of SAGE libraries, we have determined transcriptome profiles for preinvasive carcinoma-in-situ (CIS) and invasive squamous cell carcinoma (SCC) of the lung, and compared these with expression profiles generated from both bronchial epithelium, and precancerous metaplastic and dysplastic lesions using Ingenuity Pathway Analysis. Expression of genes associated with epidermal development, and loss of expression of genes associated with mucociliary biology, are predominant features of CIS, largely shared with precancerous lesions. Additionally, expression of genes associated with xenobiotic metabolism/detoxification is a notable feature of CIS, and is largely maintained in invasive cancer. Genes related to tissue fibrosis and acute phase immune response are characteristic of the invasive SCC phenotype. Moreover, the data presented here suggests that tissue remodeling/fibrosis is initiated at the early stages of CIS. Additionally, this study indicates that alteration in copy-number status represents a plausible mechanism for differential gene expression in CIS and invasive SCC.

Conclusions/significance: This study is the first report of large-scale expression profiling of CIS of the lung. Unbiased expression profiling of these preinvasive and invasive lesions provides a platform for further investigations into the molecular genetic events relevant to early stages of squamous NSCLC development. Additionally, up-regulated genes detected at extreme differences between CIS and invasive cancer may have potential to serve as biomarkers for early detection.

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Venn diagrams of differentially expressed genes discussed in this manuscript.Criteria for differential gene expression was defined as a minimal three-fold difference in normalized mean tag counts, and with a minimal mean tag abundance of 40 TPM in the over-expressing datasets. Up-arrows indicate up-regulated gene expression changes; down-arrows indicate down-regulated gene expression changes; numerical values refer to the number of differentially expressed tags. Areas of interception reflect gene expression changes in common between the two datasets. A. Expression changes in carcinoma-in-situ and precancerous lesions relative to BE. B. Expression changes in the cancer datasets relative to both bronchial epithelium and precancerous datasets. BE: bronchial epithelial; PC: precancer; CIS: carcinoma-in-situ; SCC: invasive squamous cell carcinoma.
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pone-0009162-g003: Venn diagrams of differentially expressed genes discussed in this manuscript.Criteria for differential gene expression was defined as a minimal three-fold difference in normalized mean tag counts, and with a minimal mean tag abundance of 40 TPM in the over-expressing datasets. Up-arrows indicate up-regulated gene expression changes; down-arrows indicate down-regulated gene expression changes; numerical values refer to the number of differentially expressed tags. Areas of interception reflect gene expression changes in common between the two datasets. A. Expression changes in carcinoma-in-situ and precancerous lesions relative to BE. B. Expression changes in the cancer datasets relative to both bronchial epithelium and precancerous datasets. BE: bronchial epithelial; PC: precancer; CIS: carcinoma-in-situ; SCC: invasive squamous cell carcinoma.

Mentions: Transition from a healthy bronchial epithelium to invasive cancer is thought to proceed via progression of histological and genetic abnormalities: BE to PC to CIS to SCC, where PC represents precancerous lesions (squamous metaplasia and dysplasia). Squamous metaplasia is a transient component of normal wound healing of the bronchial epithelium, and typically resolves to a re-differentiated epithelium composed of pseudostratified ciliated and secretory cells, restoring bronchial function [42]. (Use of the term PC here does not imply an obligatory progression to cancer, but rather refers to lesions/abnormalities that despite infrequent progression to cancer, are considered as precursors to cancer.) Conversely, CIS lesions demonstrate a low regression frequency with a high incidence of progression to invasive cancer [43], [44] and are characterized by a more extensive stratification of squamous cell types compared to PC [9], [11], [12]. By identifying gene expression changes common to both PC and CIS relative to BE, we focus on those genetic events which occur early and persist through to CIS. In accordance with our selection criteria (minimal three-fold difference in average normalized tag abundance; minimal average normalized tag abundance of 40 TPM in the over-expressing dataset), 868 SAGE tags were found to be similarly differentially expressed in PC and CIS relative to BE, consisting of 190 up-regulated tags, and 678 down-regulated tags (Figure 3A).


Transcriptome profiles of carcinoma-in-situ and invasive non-small cell lung cancer as revealed by SAGE.

Lonergan KM, Chari R, Coe BP, Wilson IM, Tsao MS, Ng RT, Macaulay C, Lam S, Lam WL - PLoS ONE (2010)

Venn diagrams of differentially expressed genes discussed in this manuscript.Criteria for differential gene expression was defined as a minimal three-fold difference in normalized mean tag counts, and with a minimal mean tag abundance of 40 TPM in the over-expressing datasets. Up-arrows indicate up-regulated gene expression changes; down-arrows indicate down-regulated gene expression changes; numerical values refer to the number of differentially expressed tags. Areas of interception reflect gene expression changes in common between the two datasets. A. Expression changes in carcinoma-in-situ and precancerous lesions relative to BE. B. Expression changes in the cancer datasets relative to both bronchial epithelium and precancerous datasets. BE: bronchial epithelial; PC: precancer; CIS: carcinoma-in-situ; SCC: invasive squamous cell carcinoma.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2820080&req=5

pone-0009162-g003: Venn diagrams of differentially expressed genes discussed in this manuscript.Criteria for differential gene expression was defined as a minimal three-fold difference in normalized mean tag counts, and with a minimal mean tag abundance of 40 TPM in the over-expressing datasets. Up-arrows indicate up-regulated gene expression changes; down-arrows indicate down-regulated gene expression changes; numerical values refer to the number of differentially expressed tags. Areas of interception reflect gene expression changes in common between the two datasets. A. Expression changes in carcinoma-in-situ and precancerous lesions relative to BE. B. Expression changes in the cancer datasets relative to both bronchial epithelium and precancerous datasets. BE: bronchial epithelial; PC: precancer; CIS: carcinoma-in-situ; SCC: invasive squamous cell carcinoma.
Mentions: Transition from a healthy bronchial epithelium to invasive cancer is thought to proceed via progression of histological and genetic abnormalities: BE to PC to CIS to SCC, where PC represents precancerous lesions (squamous metaplasia and dysplasia). Squamous metaplasia is a transient component of normal wound healing of the bronchial epithelium, and typically resolves to a re-differentiated epithelium composed of pseudostratified ciliated and secretory cells, restoring bronchial function [42]. (Use of the term PC here does not imply an obligatory progression to cancer, but rather refers to lesions/abnormalities that despite infrequent progression to cancer, are considered as precursors to cancer.) Conversely, CIS lesions demonstrate a low regression frequency with a high incidence of progression to invasive cancer [43], [44] and are characterized by a more extensive stratification of squamous cell types compared to PC [9], [11], [12]. By identifying gene expression changes common to both PC and CIS relative to BE, we focus on those genetic events which occur early and persist through to CIS. In accordance with our selection criteria (minimal three-fold difference in average normalized tag abundance; minimal average normalized tag abundance of 40 TPM in the over-expressing dataset), 868 SAGE tags were found to be similarly differentially expressed in PC and CIS relative to BE, consisting of 190 up-regulated tags, and 678 down-regulated tags (Figure 3A).

Bottom Line: Expression of genes associated with epidermal development, and loss of expression of genes associated with mucociliary biology, are predominant features of CIS, largely shared with precancerous lesions.Additionally, expression of genes associated with xenobiotic metabolism/detoxification is a notable feature of CIS, and is largely maintained in invasive cancer.Additionally, up-regulated genes detected at extreme differences between CIS and invasive cancer may have potential to serve as biomarkers for early detection.

View Article: PubMed Central - PubMed

Affiliation: Genetics Unit, Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.

ABSTRACT

Background: Non-small cell lung cancer (NSCLC) presents as a progressive disease spanning precancerous, preinvasive, locally invasive, and metastatic lesions. Identification of biological pathways reflective of these progressive stages, and aberrantly expressed genes associated with these pathways, would conceivably enhance therapeutic approaches to this devastating disease.

Methodology/principal findings: Through the construction and analysis of SAGE libraries, we have determined transcriptome profiles for preinvasive carcinoma-in-situ (CIS) and invasive squamous cell carcinoma (SCC) of the lung, and compared these with expression profiles generated from both bronchial epithelium, and precancerous metaplastic and dysplastic lesions using Ingenuity Pathway Analysis. Expression of genes associated with epidermal development, and loss of expression of genes associated with mucociliary biology, are predominant features of CIS, largely shared with precancerous lesions. Additionally, expression of genes associated with xenobiotic metabolism/detoxification is a notable feature of CIS, and is largely maintained in invasive cancer. Genes related to tissue fibrosis and acute phase immune response are characteristic of the invasive SCC phenotype. Moreover, the data presented here suggests that tissue remodeling/fibrosis is initiated at the early stages of CIS. Additionally, this study indicates that alteration in copy-number status represents a plausible mechanism for differential gene expression in CIS and invasive SCC.

Conclusions/significance: This study is the first report of large-scale expression profiling of CIS of the lung. Unbiased expression profiling of these preinvasive and invasive lesions provides a platform for further investigations into the molecular genetic events relevant to early stages of squamous NSCLC development. Additionally, up-regulated genes detected at extreme differences between CIS and invasive cancer may have potential to serve as biomarkers for early detection.

Show MeSH
Related in: MedlinePlus