Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer

Humam Kadara, Junya Fujimoto, Suk Young Yoo, Yuho Maki, Adam C. Gower, Mohamed Kabbout, Melinda M. Garcia, Chi Wan Chow, Zuoming Chu, Gabriella Mendoza, Li Shen, Neda Kalhor, Waun Ki Hong, Cesar Moran, Jing Wang, Avrum Spira, Kevin R. Coombes, Ignacio I. Wistuba

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Abstract

Background Earlier work identified specific tumor-promoting abnormalities that are shared between lung cancers and adjacent normal bronchial epithelia. We sought to characterize the yet unknown global molecular and adjacent airway field cancerization (FC) in early-stage non-small cell lung cancer (NSCLC). Methods Whole-transcriptome expression profiling of resected early-stage (I-IIIA) NSCLC specimens (n = 20) with matched tumors, multiple cytologically controlled normal airways with varying distances from tumors, and uninvolved normal lung tissues (n = 194 samples) was performed using the Affymetrix Human Gene 1.0 ST platform. Mixedeffects models were used to identify differentially expressed genes among groups. Ordinal regression analysis was performed to characterize site-dependent airway expression profiles. All statistical tests were two-sided, except where noted. Results We identified differentially expressed gene features (n = 1661) between NSCLCs and airways compared with normal lung tissues, a subset of which (n = 299), after gene set enrichment analysis, statistically significantly (P <.001) distinguished large airways in lung cancer patients from airways in cancer-free smokers. In addition, we identified genes (n = 422) statistically significantly and progressively differentially expressed in airways by distance from tumors that were found to be congruently modulated between NSCLCs and normal lung tissues. Furthermore, LAPTM4B, with statistically significantly increased expression (P <.05) in airways with shorter distance from tumors, was upregulated in human immortalized cells compared with normal bronchial epithelial cells (P <.001) and promoted anchorage-dependent and -independent lung cancer cell growth. Conclusions The adjacent airway FC comprises both site-independent profiles as well as gradient and localized airway expression patterns. Profiling of the airway FC may provide new insights into NSCLC oncogenesis and molecular tools for detection of the disease.

Original languageEnglish
Article numberdju004
JournalJournal of the National Cancer Institute
Volume106
Issue number3
DOIs
Publication statusPublished - 2014
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Lung Neoplasms
Neoplasms
Genes
Lung
Gene Expression Profiling
Carcinogenesis
Epithelium
Epithelial Cells
Regression Analysis
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Kadara, H., Fujimoto, J., Yoo, S. Y., Maki, Y., Gower, A. C., Kabbout, M., ... Wistuba, I. I. (2014). Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer. Journal of the National Cancer Institute, 106(3), [dju004]. https://doi.org/10.1093/jnci/dju004

Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer. / Kadara, Humam; Fujimoto, Junya; Yoo, Suk Young; Maki, Yuho; Gower, Adam C.; Kabbout, Mohamed; Garcia, Melinda M.; Chow, Chi Wan; Chu, Zuoming; Mendoza, Gabriella; Shen, Li; Kalhor, Neda; Hong, Waun Ki; Moran, Cesar; Wang, Jing; Spira, Avrum; Coombes, Kevin R.; Wistuba, Ignacio I.

In: Journal of the National Cancer Institute, Vol. 106, No. 3, dju004, 2014.

Research output: Contribution to journalArticle

Kadara, H, Fujimoto, J, Yoo, SY, Maki, Y, Gower, AC, Kabbout, M, Garcia, MM, Chow, CW, Chu, Z, Mendoza, G, Shen, L, Kalhor, N, Hong, WK, Moran, C, Wang, J, Spira, A, Coombes, KR & Wistuba, II 2014, 'Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer', Journal of the National Cancer Institute, vol. 106, no. 3, dju004. https://doi.org/10.1093/jnci/dju004
Kadara, Humam ; Fujimoto, Junya ; Yoo, Suk Young ; Maki, Yuho ; Gower, Adam C. ; Kabbout, Mohamed ; Garcia, Melinda M. ; Chow, Chi Wan ; Chu, Zuoming ; Mendoza, Gabriella ; Shen, Li ; Kalhor, Neda ; Hong, Waun Ki ; Moran, Cesar ; Wang, Jing ; Spira, Avrum ; Coombes, Kevin R. ; Wistuba, Ignacio I. / Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer. In: Journal of the National Cancer Institute. 2014 ; Vol. 106, No. 3.
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abstract = "Background Earlier work identified specific tumor-promoting abnormalities that are shared between lung cancers and adjacent normal bronchial epithelia. We sought to characterize the yet unknown global molecular and adjacent airway field cancerization (FC) in early-stage non-small cell lung cancer (NSCLC). Methods Whole-transcriptome expression profiling of resected early-stage (I-IIIA) NSCLC specimens (n = 20) with matched tumors, multiple cytologically controlled normal airways with varying distances from tumors, and uninvolved normal lung tissues (n = 194 samples) was performed using the Affymetrix Human Gene 1.0 ST platform. Mixedeffects models were used to identify differentially expressed genes among groups. Ordinal regression analysis was performed to characterize site-dependent airway expression profiles. All statistical tests were two-sided, except where noted. Results We identified differentially expressed gene features (n = 1661) between NSCLCs and airways compared with normal lung tissues, a subset of which (n = 299), after gene set enrichment analysis, statistically significantly (P <.001) distinguished large airways in lung cancer patients from airways in cancer-free smokers. In addition, we identified genes (n = 422) statistically significantly and progressively differentially expressed in airways by distance from tumors that were found to be congruently modulated between NSCLCs and normal lung tissues. Furthermore, LAPTM4B, with statistically significantly increased expression (P <.05) in airways with shorter distance from tumors, was upregulated in human immortalized cells compared with normal bronchial epithelial cells (P <.001) and promoted anchorage-dependent and -independent lung cancer cell growth. Conclusions The adjacent airway FC comprises both site-independent profiles as well as gradient and localized airway expression patterns. Profiling of the airway FC may provide new insights into NSCLC oncogenesis and molecular tools for detection of the disease.",
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AU - Kadara, Humam

AU - Fujimoto, Junya

AU - Yoo, Suk Young

AU - Maki, Yuho

AU - Gower, Adam C.

AU - Kabbout, Mohamed

AU - Garcia, Melinda M.

AU - Chow, Chi Wan

AU - Chu, Zuoming

AU - Mendoza, Gabriella

AU - Shen, Li

AU - Kalhor, Neda

AU - Hong, Waun Ki

AU - Moran, Cesar

AU - Wang, Jing

AU - Spira, Avrum

AU - Coombes, Kevin R.

AU - Wistuba, Ignacio I.

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N2 - Background Earlier work identified specific tumor-promoting abnormalities that are shared between lung cancers and adjacent normal bronchial epithelia. We sought to characterize the yet unknown global molecular and adjacent airway field cancerization (FC) in early-stage non-small cell lung cancer (NSCLC). Methods Whole-transcriptome expression profiling of resected early-stage (I-IIIA) NSCLC specimens (n = 20) with matched tumors, multiple cytologically controlled normal airways with varying distances from tumors, and uninvolved normal lung tissues (n = 194 samples) was performed using the Affymetrix Human Gene 1.0 ST platform. Mixedeffects models were used to identify differentially expressed genes among groups. Ordinal regression analysis was performed to characterize site-dependent airway expression profiles. All statistical tests were two-sided, except where noted. Results We identified differentially expressed gene features (n = 1661) between NSCLCs and airways compared with normal lung tissues, a subset of which (n = 299), after gene set enrichment analysis, statistically significantly (P <.001) distinguished large airways in lung cancer patients from airways in cancer-free smokers. In addition, we identified genes (n = 422) statistically significantly and progressively differentially expressed in airways by distance from tumors that were found to be congruently modulated between NSCLCs and normal lung tissues. Furthermore, LAPTM4B, with statistically significantly increased expression (P <.05) in airways with shorter distance from tumors, was upregulated in human immortalized cells compared with normal bronchial epithelial cells (P <.001) and promoted anchorage-dependent and -independent lung cancer cell growth. Conclusions The adjacent airway FC comprises both site-independent profiles as well as gradient and localized airway expression patterns. Profiling of the airway FC may provide new insights into NSCLC oncogenesis and molecular tools for detection of the disease.

AB - Background Earlier work identified specific tumor-promoting abnormalities that are shared between lung cancers and adjacent normal bronchial epithelia. We sought to characterize the yet unknown global molecular and adjacent airway field cancerization (FC) in early-stage non-small cell lung cancer (NSCLC). Methods Whole-transcriptome expression profiling of resected early-stage (I-IIIA) NSCLC specimens (n = 20) with matched tumors, multiple cytologically controlled normal airways with varying distances from tumors, and uninvolved normal lung tissues (n = 194 samples) was performed using the Affymetrix Human Gene 1.0 ST platform. Mixedeffects models were used to identify differentially expressed genes among groups. Ordinal regression analysis was performed to characterize site-dependent airway expression profiles. All statistical tests were two-sided, except where noted. Results We identified differentially expressed gene features (n = 1661) between NSCLCs and airways compared with normal lung tissues, a subset of which (n = 299), after gene set enrichment analysis, statistically significantly (P <.001) distinguished large airways in lung cancer patients from airways in cancer-free smokers. In addition, we identified genes (n = 422) statistically significantly and progressively differentially expressed in airways by distance from tumors that were found to be congruently modulated between NSCLCs and normal lung tissues. Furthermore, LAPTM4B, with statistically significantly increased expression (P <.05) in airways with shorter distance from tumors, was upregulated in human immortalized cells compared with normal bronchial epithelial cells (P <.001) and promoted anchorage-dependent and -independent lung cancer cell growth. Conclusions The adjacent airway FC comprises both site-independent profiles as well as gradient and localized airway expression patterns. Profiling of the airway FC may provide new insights into NSCLC oncogenesis and molecular tools for detection of the disease.

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