Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

作者：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 · 发表于：PLoS ONE · 年份：2012 · DOI：10.1371/journal.pone.0036530 · 被引用次数：310 · 研究领域：Lung Cancer Treatments and Mutations、Lung Cancer Diagnosis and Treatment、Cancer Genomics and Diagnostics

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 K...