Abstract LB-439: Distinct tumorigenic pathways within the hereditary nonpolyposis colorectal cancer
Authors: Valentin Mev D. , Therkildsen Christina , Veerla Srinivas , Jonsson Mats , Jönsson Göran , Bernstein Inge , Nilbert Mef 
Published: August 2012

Background Identification of families with hereditary nonpolyposis colorectal cancer (HNPCC) allows for surveillance that has been proved to reduce morbidity and mortality from colorectal cancer (CRC). The HNPCC subset can broadly be divided into tumors caused by germline mismatch-repair (MMR) gene mutations, referred to as Lynch syndrome (LS), and those with an undefined genetic background, designated as familial colorectal cancer type X (FCC-X). Recognition of FCC-X tumor is challenging due to the lack of MMR defect and limited information is available about the global gene expression patterns in FCC-X tumors. We aimed at comprehensive pathway mapping of the global gene expression profile in FCC-X tumors with comparison to LS and sporadic CRC as controls. Materials and methods Tumour specimens were obtained from the national Danish HNPCC Register. RNA was extracted from 3-5 10-µm sections using the High Pure RNA Paraffin Kit (Roche, Castle Hill, Australia). The Whole-genome cDNA-mediated annealing selection extension and ligation (DASL) assay (Illumina, San Diego, CA) containing &gt;24,000 probes in &gt;18,000 genes was used for whole genome expression analysis. Expression values were analysed using the GenomeStudio software (Illumina, San Diego, CA) and imported into MeV 4.6.02. Canonical pathways were identified using DAVID Bioinformatics Resources 6.7. Results RNA was obtained from 180 tumors (60 LS, 60 FCC-X, 30 sporadic MSI-CRC and 30 sporadic MSS-CRC. Samples with &lt;7000 genes represented (n=48) were excluded. Expression data from the remaining 132 samples were cubic normalized and a presence filter of 80% was applied (detection p-values ≤0.01). Sequence Alignment and Modeling (SAM) system analysis identified 3873 genes that differed significantly between LS/sporadic MSI-CRC and FCC-X/sporadic MSS-CRC. Using DAVID Bioinformatics resources, we identified 5 significantly up-regulated pathways in FCC-X/MSS-CRC including vascular smooth muscle contraction, G-protein coupled receptor signaling, calcium signaling, Wnt signalling and integrin cell surface interactions. For LS/MSI-CRC, we also identified 5 up-regulated pathways related antigen processing and presentation, DNA replication, cell cycle progression, and telomere maintenance. Conclusions Gene expression profiling using the DASL technology from 132 CRC identified MSI status as the major discriminator. Our data indicates that vascular smooth muscle contraction, G-protein coupled receptor signaling, calcium signaling, Wnt signaling, and integrin cell surface interactions pathways are up-regulated in FCC-X and MSS-CRC. These data provide strong evidence that these pathways play a role in development of CRC in these families and FCC-X should be considered as different clinical entity. These data also identify key signaling pathways as potential therapeutic targets in FCC- X tumors.

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-439. doi:1538-7445.AM2012-LB-439