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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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Correlation between up-regulated gene expression in CIS and SCC relative to BE and PC, with regions of frequent copy-number gain in CIS specimens.Up-regulated genes (x-axis), plotted according to chromosomal location as indicated, were matched with segmental copy-number status (y-axis), defined by frequent copy-number gain (blue) and loss (red), from 20 independent CIS specimens. 224 genes were analyzed, and only those associated with regions gained at a minimal frequency of 0.2 are shown above. Knowledge of losses in addition to gains serves as a filter to identify those chromosomal regions that are preferentially gained rather than a reflection of general instability. See Table S12 for raw data pertaining to these analyses.
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pone-0009162-g007: Correlation between up-regulated gene expression in CIS and SCC relative to BE and PC, with regions of frequent copy-number gain in CIS specimens.Up-regulated genes (x-axis), plotted according to chromosomal location as indicated, were matched with segmental copy-number status (y-axis), defined by frequent copy-number gain (blue) and loss (red), from 20 independent CIS specimens. 224 genes were analyzed, and only those associated with regions gained at a minimal frequency of 0.2 are shown above. Knowledge of losses in addition to gains serves as a filter to identify those chromosomal regions that are preferentially gained rather than a reflection of general instability. See Table S12 for raw data pertaining to these analyses.

Mentions: To investigate whether alterations in gene dosage contributes mechanistically to the differential gene expression identified here in early-stage lung cancer, we compared segmental copy number gain/loss from 20 independent CIS specimens with locus information for up-regulated and down-regulated genes in CIS/SCC relative to BE and PC. A subset of up-regulated genes localized to regions of stable frequent gain (Figure 7), and a subset of down-regulated genes localized to regions of stable frequent loss (Figure 8). Most prominently identified corresponding regions of copy number gain include 1q21–1q42.13 and 3q12.1–3q29, and loci within chromosomal arms 7q, 8q, 17q, and 20q. It is noted that the region 1q21 encodes the EDC, a region over-expressed early in CIS lesions (see above). Most prominently identified corresponding regions of copy number loss include loci within chromosomal arms 3p and 6p. This data agrees with previously published data for lung cancer, particularly amplification at 3q, 7q, 8q, and loss of 3p [146], [147], [148]. [Notably, a recent study describes genomic amplification and over-expression of transcription factor SOX2 encoded at 3q26.33 in lung squamous cell carcinoma [149]. Although we detect enhanced expression of SOX2 in CIS relative to both BE and PC, the tag abundance ratio falls marginally below the three-fold threshold/cut-off applied in this study, precluding this gene from the copy-number analysis presented here.] The data presented here suggests that frequent chromosomal gain/loss of specific loci, represents a significant mechanism for differential gene expression in early, preinvasive stages of squamous cell lung cancer. See Table S12 and Table S13 for raw data describing copy-number status for up-regulated genes and down-regulated genes, respectively.


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)

Correlation between up-regulated gene expression in CIS and SCC relative to BE and PC, with regions of frequent copy-number gain in CIS specimens.Up-regulated genes (x-axis), plotted according to chromosomal location as indicated, were matched with segmental copy-number status (y-axis), defined by frequent copy-number gain (blue) and loss (red), from 20 independent CIS specimens. 224 genes were analyzed, and only those associated with regions gained at a minimal frequency of 0.2 are shown above. Knowledge of losses in addition to gains serves as a filter to identify those chromosomal regions that are preferentially gained rather than a reflection of general instability. See Table S12 for raw data pertaining to these analyses.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2820080&req=5

pone-0009162-g007: Correlation between up-regulated gene expression in CIS and SCC relative to BE and PC, with regions of frequent copy-number gain in CIS specimens.Up-regulated genes (x-axis), plotted according to chromosomal location as indicated, were matched with segmental copy-number status (y-axis), defined by frequent copy-number gain (blue) and loss (red), from 20 independent CIS specimens. 224 genes were analyzed, and only those associated with regions gained at a minimal frequency of 0.2 are shown above. Knowledge of losses in addition to gains serves as a filter to identify those chromosomal regions that are preferentially gained rather than a reflection of general instability. See Table S12 for raw data pertaining to these analyses.
Mentions: To investigate whether alterations in gene dosage contributes mechanistically to the differential gene expression identified here in early-stage lung cancer, we compared segmental copy number gain/loss from 20 independent CIS specimens with locus information for up-regulated and down-regulated genes in CIS/SCC relative to BE and PC. A subset of up-regulated genes localized to regions of stable frequent gain (Figure 7), and a subset of down-regulated genes localized to regions of stable frequent loss (Figure 8). Most prominently identified corresponding regions of copy number gain include 1q21–1q42.13 and 3q12.1–3q29, and loci within chromosomal arms 7q, 8q, 17q, and 20q. It is noted that the region 1q21 encodes the EDC, a region over-expressed early in CIS lesions (see above). Most prominently identified corresponding regions of copy number loss include loci within chromosomal arms 3p and 6p. This data agrees with previously published data for lung cancer, particularly amplification at 3q, 7q, 8q, and loss of 3p [146], [147], [148]. [Notably, a recent study describes genomic amplification and over-expression of transcription factor SOX2 encoded at 3q26.33 in lung squamous cell carcinoma [149]. Although we detect enhanced expression of SOX2 in CIS relative to both BE and PC, the tag abundance ratio falls marginally below the three-fold threshold/cut-off applied in this study, precluding this gene from the copy-number analysis presented here.] The data presented here suggests that frequent chromosomal gain/loss of specific loci, represents a significant mechanism for differential gene expression in early, preinvasive stages of squamous cell lung cancer. See Table S12 and Table S13 for raw data describing copy-number status for up-regulated genes and down-regulated genes, respectively.

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