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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Yin
authors.forename: Vonn
authors.initials: V
authors.lastname: Walter
authors.forename: Ni
authors.initials: N
authors.lastname: Zhao
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cabanski
authors.forename: Michele C
authors.initials: MC
authors.lastname: Hayward
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.forename: Alden M
authors.initials: AM
authors.lastname: Parsons
authors.forename: Leigh B
authors.initials: LB
authors.lastname: Thorne
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Haithcock
authors.forename: Nirmal K
authors.initials: NK
authors.lastname: Veeramachaneni
authors.forename: William K
authors.initials: WK
authors.lastname: Funkhouser
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.forename: Philip S
authors.initials: PS
authors.lastname: Bernard
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000368:Aged; D043171:Chromosomal Instability; D015331:Cohort Studies; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015996:Survival Rate
chemical_list: D004273:DNA, Neoplasm