Introduction: Lung adenocarcinoma is a clinically and genetically heterogenous disease. Recently, three validated and clinically relevant gene expression subtypes (Magnoid, Bronchioid, and Squamoid) have been described (Hayes, 2006); however, the subtypes’ origins are unknown. We hypothesized that the subtypes are the result of unique gene mutations and DNA copy number alterations in unique patient populations.

Methods: 85 lung adenocarcinomas were collected and assayed for gene expression and DNA copy number (CN), using Agilent 44K and Affymetrix 250K_Sty microarrays. 376 lung adenocarcinomas with gene expression microarrays and CN arrays or gene mutations were obtained from three published cohorts (Ding, 2008; Tomida, 2009; Chitale, 2009). Tumor subtype classification was completed using published methods. CN was calculated and significantly altered CN segments were detected (Beroukhim, 2007; Bengtsson, 2008). Subtype segment CN was compared by z -scores (FDR < 1%). Mutations and clinical variables were compared by Cochran-Mantel-Haenszel tests adjusting for cohort and by Kruskal-Wallace tests. Subtype 3-year survival was compared by log rank tests and Cox proportional hazards models adjusted by cohort.

Results: Three gene expression subtypes were detected in each of four cohorts and uniquely corresponded to the known Magnoid (M), Bronchioid (B) and Squamoid (S) subtypes. Gene mutations were significantly associated with subtype, including EGFR increased in B (M/B/S: 16%, 39%, 23%; P ≪ 0.01) and TP53 increased in M (M/B/S: 45%, 24%, 15%; P ≪ 0.01). Additionally, numerous genomic regions had significantly different mean DNA copy number across the subtypes including amplifications (M: 3q26, 7q31; B: 5q34, 16p13) and deletions (M: 4q35.1, 17p12). Interestingly, a more broad measure of overall genomic stability (chromosome arm variation) was also significantly different among subtypes, with M having the highest instability (P ≪ 0.01). In terms of clinical significance, 3-year subtype patient survival was significantly different (M/B/S − 66%, 87%, 83%; P ≪ 0.01), and remained so after adjustment for mutations, stage, and sex. Patient smoking history was significantly different among the subtypes (pack year median M/B/S: 40/10/34; P ≪ 0.01). Also, previously reported associations of subtype and morphology were confirmed, with lower grade (P ≪ 0.01) and increased micropapillary features in B (P = 0.04).

Conclusions: Lung adenocarcinoma gene expression subtypes have different levels of EGFR and TP53 gene mutations, global genomic instability, specific DNA copy number alterations, and clinical and morphologic characteristics. This integrated analysis supports that different mutation events in concert with different patient populations contribute to produce these distinct and clinically relevant gene expression subtypes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2164.