Molecular pathology of colorectal cancer predisposing syndromes

T. van Wezel, J.Th. Wijnen, (Dept Human Genetics) and. H. Morreau,  

Clinical genetics centers in the Netherlands receive many requests for counseling and advice about increased risk for colorectal cancer (CRC) in the family. In many cases predisposing genes for these cases are not identified. CRC is the third most important cancer type according to prevalence and mortality in the western world. Predisposition to CRC is influenced by both environmental and genetic factors. Approximately 15-30% of all CRC cases show familial clustering of which only up to 5 percent can be explained by inherited mutations, mostly in APC, the mismatch repair genes, or the recently identified MYH. For the remaining familial CRC cases the underlying genetics remain elusive. Although combinations of low penetrant modifier genes with low relative risk could in part explain increased susceptibility to CRC, the presence of yet unidentified gene-mutations with moderate or even high penetrance is indicated by Hereditary Nonpolyposis Colorectal Cancer (HNPCC)-like families, with clear dominant patterns of inheritance but without mutations in the MMR-genes. The hallmark of HNPCC, microsatellite instability (MSI) is absent in tumors in ~30% of all families fulfilling the clinical criteria for HNPCC. These tumors lack MMR-mutations and show normal MMR-protein expression suggesting the involvement of a different class or classes of genes. Candidate CRC genes are too numerous to be screened one-by-one, without any preselection such as genome-wide linkage and/or LOH analysis.  

We want to identify new predisposing genes with moderate or high penetrance, in families with strong clustering of CRC employing different strategies of preselection. 

We will use linkage analysis, supported by high-resolution chromosomal profiling in MMR-mutation negative Amsterdam II criteria positive families with microsatellite-stable (MSS) tumors to preselect genomic regions where CRC predisposing genes reside. During the last 20 years we have collected a series of 33 mutation-negative HNPCC-families with MMR proficient tumors. Due to the long follow up of these families, seven families individually gained enough power to detect significant linkage with predisposing genes. Additionally ~650 MSS tumors from suspect-HNPCC cases are available for analysis. 

The identification of novel genes that are mutated in familial CRC can directly be implemented in the counseling of predisposed families, and will identify the individuals that have an increased genetic risk for cancer in these families. Timely and efficient surveillance through colonoscopy, and subsequent removal of precursor lesions (the adenomatous polyps) or colorectal carcinoma in early stages improves survival rates, and prevents CRC. 

Funded by the Dutch Cancer Society Grant UL 2005-3247