Large intestine cancer

Colorectal cancer (CRC) is a somatic evolutionary process starting from a germline risk profile and leading to a somatic signature of genetic and epigenetic changes in the tumor cell. Monogenic forms (HNPCC, FAP) account for ~5% of CRC. The CCN (Colorectal Cancer Network) will focus on the genomic investigation of both the germline and somatic DNA signature and their functional consequences in non-syndromatic CRC. CRC shows a well documented age-dependent familial clustering, indicating the existence of germline risk variants reported in newly published genome-wide scans. In the present project these results are used in large-scale SNP genotyping and copy-number analysis in N>5000 patients within the consortium. Disease variants will be evaluated in a population based setting which allows assessment of gene-environment and gene-gene interactions. Many of the newly detected variants have no known function and an effort is made to find the true (rare) variants by sequencing around the candidate loci among the affected individuals. In search for somatic mutations, a clinically homogenous set of CRC tumors will be comprehensively characterized by whole-transcriptome sequencing, genome-wide methylation assays and SNP-chip based imbalance and loss of heterozygosity (LOH) mapping. A tissue bank of fresh frozen tumor samples and additional paraffin blocks is available for follow-up of the identified carcinogenesis “driver” events. A functional and systems biology agenda using allelic expression systems, systematic cellular assays and RNAi screening will work to develop an integrated model of human colon cancer etiology and pathogenesis. Both genetic epidemiology and systems biology groups are involved in the modelling. Many cancer-related genes were initially identified in family studies and they were later shown to be commonly mutated even in sporadic tumors. The present network structure allows a ready testing of the familial candidate genes for somatic mutations and vice versa.


Summary of the Kiel activities in den CCN:

The Colon Cancer Network is localized at two major sites: Heidelberg and Kiel. The Kiel projects (TP1, 3, 5, 8) work in close interaction with the colleagues in Heidelberg. Kiel provides the major patient ressources for the germline agendas with its cohort of over 3000 colon cancer patients. As part of the CCN, a characterization of the long-term course of the disorder in these patients is undertaken. Project 8 provides the tissue bank support for the whole network through the surgical biobank in Kiel. Molecular agendas are based on the established expertise in complex disease cloning and somatic genetics and aim to elucidate the mechanisms of cancerogenesis in colon cancer as a basis for future therapies and better diagnostics. The activities of the Kiel site are coordinated by PD Dr. Jochen Hampe (Genomic Gastroenterology Group, Department of General Internal Medicine).