Abstract 5170: Linking tumor evolution and therapy response using diagnostic targeted next generation sequencing in colorectal cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-10, Vol.74 (19_Supplement), p.5170-5170
• Main Authors: Mamlouk, Soulafa, Childs, Liam, Redmer, Thorben, Durek, Pawel, Schumacher, Dirk, Bläker, Hendrik, Aust, Daniela, Winterfeld, Moritz von, Heinemann, Volker, Modest, Dominik, Möhr, Kerstin, Morkel, Markus, Schäfer, Reinhold, Sers, Christine
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-5170

Complex sets of driver mutations critically control clinical course and treatment response in colorectal cancer (CRC). It is expected that multiple mutations in different signaling pathways interact to establish an individual cancer cell phenotype. Furthermore, mutational patterns can evolve under selective pressure, for instance during tumor metastasis or targeted therapy. Yet only few mutations, such as these in KRAS, NRAS and BRAF, are routinely assessed in the clinic today. With the introduction of next generation sequencing (NGS) many more genes can be simultaneously sequenced, allowing detailed analyses of mutational patterns. We have assembled the CRC5.2 NGS panel for application with Ion Torrent PGM covering 100 frequently mutated genes with 784 amplicons (covering 21,000 COSMIC mutations), going well beyond the scope of commercially available cancer panels. In particular, exon coverage was optimized to embrace all genomic information related to drug sensitivity, using several drug and signaling network databases. The German Consortium for Translational Cancer Research (DKTK) comprises the top cancer centers in Germany. As a part of this group, we employ our custom CRC5.2 panel for the analysis of mutational patterns in CRC. We address several key questions relevant for current diagnostics and treatment in colorectal cancer. In retrospective and prospective clinical studies, we assess mutational heterogeneity in primary tumors, synchronous and metachronous metastases of individual patients. In-depth NGS mutational analyses, transcriptome analysis and methylation studies will identify (epi-)genetic alterations occurring as a consequence of selective pressure during tumor evolution e.g. during metastasis, chemotherapy or targeted tumor therapy. Thus, we will uncover new links between cancer-specific mutations, clinical course and treatment response as well as novel mechanisms of secondary resistance. In addition we aim to identify novel predictive and prognostic mutational markers for the benefit of future CRC patients Citation Format: Soulafa Mamlouk, Liam Childs, Thorben Redmer, Pawel Durek, Dirk Schumacher, Hendrik Bläker, Daniela Aust, Moritz von Winterfeld, Volker Heinemann, Dominik Modest, Kerstin Möhr, Markus Morkel, Reinhold Schäfer, Christine Sers. Linking tumor evolution and therapy response using diagnostic targeted next generation sequencing in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Asso