Abstract
BackgroundGene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification.MethodsMutational status of EGFR, KRAS, and TP53 was used to define seven mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma.ResultsThe proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with co-mutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival.ConclusionsThe mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into seven subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.
Highlights
Gene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications
The mutational status of EGFR, KRAS, and TP53 can be used to classify lung adenocarcinoma patients into six subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously
We developed a simplified molecular subtype classification based on the mutational status of only EGFR, KRAS, and TP53 to facilitate categorization of patients’ lung adenocarcinomas into molecular subtypes with relevant prognostic information
Summary
Gene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. Gene expression profiling of lung adenocarcinomas has consistently identified three molecular subtypes with prognostic implications[7,8,9,10,11,12,13,14]. The initial molecular classification of lung adenocarcinomas included the bronchoid, magnoid, and squamoid subtypes[11,15]. After comprehensive molecular profiling of a cohort of lung adenocarcinomas, The Cancer Genome Atlas Research Network proposed an updated nomenclature for this molecular classification that encompasses previous histopathologic, anatomic, and mutational classifications[13]. This system re-designated the initial subtypes as the terminal respiratory unit, proximal-proliferative, and proximal-inflammatory subtypes, respectively[13]
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