Abstract LB-396: Molecular characterization of ED-SCLC: high-resolution SNP 6.0 arrays, mRNA expression, and miRNA arrays from the phase III GALES trial
Authors: Edwin Sandanaraj, Scott P. Myrand, Amit Aggarwal, Susan C. Guba, David Ohannesian, Jian WJ Wang, Yong YY Yang, Giorgio V. Scagliotti, Egbert F. Smit
Journal: Cancer Research (2012)

Abstract Background Extensive-stage disease, small-cell lung cancer (ED-SCLC) is a lethal disease with poor clinical outcomes given current systemic therapy options. The objective of this study was to examine potential prognostic factors identifiable through genome-wide characterization methodologies to enhance our current understanding of ED-SCLC and gene networks involved in ED-SCLC. Methods Patient samples obtained within the framework of a randomized Phase III trial (n=908) were successfully assayed for copy number variations (CNVs, n=92), exon array gene expression (n=73), and miRNA array (n=92). The CNV data were adjusted to account for degraded nucleic acids from formalin-fixed, paraffin-embedded samples, and copy number was estimated using the Partek® genomics suite. Unsupervised clustering analysis of exon array data was performed to detect groups of samples with similar expression profiles. Cluster stability was assessed by using bootstrapping procedures, and its association with survival was studied. For miRNAs, which were expressed in &amp;gt;75% of samples, a rank-based correlation analysis was performed between the miRNA expression and mRNA expression. A Cox-regression model was built to calculate miRNAs’ association with survival time. Results A SNP array analysis revealed CNVs at chromosomes 3p, 4q, 5q, 10q, 13q, and 17p, which was in accordance with previous reports. Novel changes at other chromosomal sites are being analyzed. Cluster analysis of expression data suggests the presence of 2 distinct molecular subtypes within the ED-SCLC patient samples examined in this analysis. A significant difference in progression-free survival (PFS) was observed (log rank, p ≤ 0.009); the median PFS for patients belonging to cluster 1 was 5.2 months versus 3.5 months for patients assigned to cluster 2. Cluster 1 showed high expression of genes associated with antiapoptotic pathways through NFKB, I-KB, IRAK1 and IRAK2; Gn-Rh signaling and downstream MAPK induction; and EGR1 factor signaling cascades, including c-Jun and c-Fos. Cluster 2 showed high expression of genes associated with DNA damage repair including ATM, MSH2, BRIP1, Rad50, and MRN complex; and G2/M checkpoint arrest through ATM phosphorylation and cyclin-B induction. Several miRNAs were associated with improved survival, including miRNAs from the miR7 and miR320 families. Conclusions This analysis of ED-SCLC patient samples, which used multiple genomics platforms, confirmed several known aberrations and identified novel markers not previously described with ED-SCLC outcomes. Two clusters of patients with distinct molecular profiles and outcomes were revealed, and miRNAs associated with improved survival outcomes were identified. While these data are exploratory and ongoing, confirmation of these observations may lead to advances in profiling and targeting important genes integral to SCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-396. doi:1538-7445.AM2012-LB-396