Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation

Matthew D. Wilkerson, Xiaoying Yin, Vonn Walter, Ni Zhao, Christopher R. Cabanski, Michele C. Hayward, C. Ryan Miller, Mark A. Socinski, Alden M. Parsons, Leigh B. Thorne, Benjamin E. Haithcock, Nirmal K. Veeramachaneni, William K. Funkhouser, Scott H. Randell, Philip S. Bernard, Charles M. Perou, D. Neil Hayes

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Abstract

Background: Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors. Methodology/Principal Findings: The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes. Conclusions/ Significance: The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.

Original languageEnglish (US)
Article numbere36530
JournalPloS one
Volume7
Issue number5
DOIs
StatePublished - May 10 2012

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Chromosomal Instability
Methylation
adenocarcinoma
methylation
Tumors
pathogenesis
Genes
lungs
mutation
Mutation
neoplasms
Gene expression
therapeutics
Cisplatin
Amplification
Neoplasms
Statistical methods
genes
Association reactions
cisplatin

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Wilkerson, Matthew D. ; Yin, Xiaoying ; Walter, Vonn ; Zhao, Ni ; Cabanski, Christopher R. ; Hayward, Michele C. ; Miller, C. Ryan ; Socinski, Mark A. ; Parsons, Alden M. ; Thorne, Leigh B. ; Haithcock, Benjamin E. ; Veeramachaneni, Nirmal K. ; Funkhouser, William K. ; Randell, Scott H. ; Bernard, Philip S. ; Perou, Charles M. ; Hayes, D. Neil. / Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation. In: PloS one. 2012 ; Vol. 7, No. 5.
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title = "Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation",
abstract = "Background: Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors. Methodology/Principal Findings: The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes. Conclusions/ Significance: The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.",
author = "Wilkerson, {Matthew D.} and Xiaoying Yin and Vonn Walter and Ni Zhao and Cabanski, {Christopher R.} and Hayward, {Michele C.} and Miller, {C. Ryan} and Socinski, {Mark A.} and Parsons, {Alden M.} and Thorne, {Leigh B.} and Haithcock, {Benjamin E.} and Veeramachaneni, {Nirmal K.} and Funkhouser, {William K.} and Randell, {Scott H.} and Bernard, {Philip S.} and Perou, {Charles M.} and Hayes, {D. Neil}",
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Wilkerson, MD, Yin, X, Walter, V, Zhao, N, Cabanski, CR, Hayward, MC, Miller, CR, Socinski, MA, Parsons, AM, Thorne, LB, Haithcock, BE, Veeramachaneni, NK, Funkhouser, WK, Randell, SH, Bernard, PS, Perou, CM & Hayes, DN 2012, 'Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation', PloS one, vol. 7, no. 5, e36530. https://doi.org/10.1371/journal.pone.0036530

Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation. / Wilkerson, Matthew D.; Yin, Xiaoying; Walter, Vonn; Zhao, Ni; Cabanski, Christopher R.; Hayward, Michele C.; Miller, C. Ryan; Socinski, Mark A.; Parsons, Alden M.; Thorne, Leigh B.; Haithcock, Benjamin E.; Veeramachaneni, Nirmal K.; Funkhouser, William K.; Randell, Scott H.; Bernard, Philip S.; Perou, Charles M.; Hayes, D. Neil.

In: PloS one, Vol. 7, No. 5, e36530, 10.05.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation

AU - Wilkerson, Matthew D.

AU - Yin, Xiaoying

AU - Walter, Vonn

AU - Zhao, Ni

AU - Cabanski, Christopher R.

AU - Hayward, Michele C.

AU - Miller, C. Ryan

AU - Socinski, Mark A.

AU - Parsons, Alden M.

AU - Thorne, Leigh B.

AU - Haithcock, Benjamin E.

AU - Veeramachaneni, Nirmal K.

AU - Funkhouser, William K.

AU - Randell, Scott H.

AU - Bernard, Philip S.

AU - Perou, Charles M.

AU - Hayes, D. Neil

PY - 2012/5/10

Y1 - 2012/5/10

N2 - Background: Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors. Methodology/Principal Findings: The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes. Conclusions/ Significance: The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.

AB - Background: Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors. Methodology/Principal Findings: The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes. Conclusions/ Significance: The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.

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