Abstract 3154: Genomic landscape of metastatic colorectal cancer.

Abstract

Abstract Background: Colorectal cancer (CRC) results from the accumulation of multiple genetic and epigenetic alterations in the genome of colorectal epithelial cells. Next to large genomic DNA copy number changes, small focal alterations can be identified, often enriched for known cancer genes. However, not all tumors present the same pattern of alterations, as CRC is a heterogeneous disease. The varying underlying biology results in different clinical outcomes, such as response to treatment. The present study aimed to document the landscape of DNA copy number changes, with special focus on focal alterations, in primary tumors of a defined subset of colorectal cancer patients who develop metastatic disease and are eligible for systemic treatment. Material and methods: Tumors were selected from mCRC patients, who participated in two Dutch multicenter phase III clinical trials, i.e. CAIRO and CAIRO2 and were treated according to three different regimens . For all patients well-defined clinical data is available. Alterations were analyzed by high-resolution array comparative genomic hybridization (aCGH), with DNA isolated from formalin-fixed paraffin-embedded (FFPE) archival blocks of 349 patients. As a reference matched normal germ-line material was used. In this way only tumor specific alterations were identified. Also, frequent copy number variations present in the general population can be distinguished from actual somatic alterations. Results: Most frequently observed large chromosomal alterations were losses of chromosomes 8p and 18 and gains of chromosomes 7, 8q 13, and 20. Seven genomic regions were significantly associated with progression free survival (PFS). The focal alterations detected are significantly enriched for cancer genes and genes frequently mutated in colorectal cancer. The gene list includes PTEN, TP53, PARK2, A2BP2 and ATBP2 located in focal losses. On focal amplifications known drugtargets such as ERBB2, EGFR and VEGF were found. Conclusion: Based on initial results we hypothesize that DNA copy number profiling may be used for therapy selection and to guide individualized anticancer therapy. Chromosomal copy number alterations in CRC have been related to response to treatment. Moreover focal alterations were enriched for cancer genes. This study was performed within the framework of CTMM, the Center for Translational Molecular Medicine Citation Format: Oscar Krijgsman, Josien Haan, Beatriz Carvalho, Gerrit A. Meijer, Bauke Ylstra. Genomic landscape of metastatic colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3154. doi:10.1158/1538-7445.AM2013-3154