Abstract 4839: Lung cancer patients exhibit a genomewide chromosomal instability and DNA methylation correlation which varies by expression subtype
Authors: Wilkerson Matthew D. , Yin Xiaoying , Hayward Michele C. , Veeramachaneni Nirmal K. , Haithcock Benjamin E. , Funkhouser William K. , Thorne Leigh , Miller C Ryan , Randell Scott H. , Hayes David N. 
Published: June 2012

Introduction: Lung cancer is a deadly disease, which manifests gross DNA alterations. Chromosome instability (CIN) and DNA methylation (DM) instability are important DNA alteration processes that contribute to the initiation and progression of lung cancer. Considering that DNA replication and methylation maintenance are coordinated, we hypothesized that CIN and DM may be coordinated in the etiology of lung cancer patients.

Methods: A cohort of 63 patients with surgically-resected lung tumors was collected. DNA copy number was measured by Affymetrix 250K_StyI microarrays. DNA methylation was measured by the MSNP assay, which involves comparing the copy number of HpaII (methylation sensitive) digested DNA to undigested DNA (Yuan, 2006). The sample genomewide CIN score was the median of chromosome arm absolute copy numbers. The sample genomewide DNA methylation score was the median of the percent methylation across all probes. mRNA expression was measured by Agilent 44K microarrays.

Results: CIN and DM varied substantially over lung cancers. Histological classes did not differ in CIN or DM. Lung cancer mRNA expression subtypes (described in Hayes et al., J Clin Oncol, 2006 and Wilkerson et al., Clin Cancer Res 2010) were significantly different in CIN (P&lt;0.05) with the magnoid adenocarcinoma, classical squamous cell carcinoma (SCC), and basal SCC subtypes having the largest CIN scores. DM was also significantly different between expression subtypes (P&lt;0.05), with the magnoid adenocarcinoma and the classical SCC having the largest DM scores. CIN and DM were significantly positively correlated (0.37; P&lt;0.01), indicating that the most copy number disrupted genomes were also the most DNA hypermethylated. To evaluate the combined effect of these alterations, a combined CIN and DM (CIN+DM) standardized score was evaluated. Histological classes did not differ in CIN+DM. Expression subtypes were significantly different in CIN+DM (P&lt;0.01) with the magnoid adenocarcinoma subtype and the classical SCC subtype exhibiting the largest CIN+DM scores. Patients with distant recurrences had a trend of larger CIN+DM scores than patients with local recurrences or no observed recurrences (P&lt;0.21). An mRNA expression signature based on the CIN+DM score was positively correlated (GSEA, FDR &lt; 0.05) with overexpression of DNA repair pathways, providing corroborating evidence for this DNA alteration phenotype.

Conclusions: Genomewide chromosomal instability and DNA methylation are significantly correlated in lung cancer. These co-occurring DNA alterations are the most extreme in the magnoid adenocarcinoma and classical squamous cell carcinoma subtypes, suggesting the subtypes have evolved differently. These results elucidate new lung cancer etiology and future therapies could be focused on exploiting these DNA alterations.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4839. doi:10.1158/1538-7445.AM2011-4839