Significance of genetic and epigenetic mechanisms and gene-environment interactions in alternative pathways of colon cancer development
Department of Pathology and Lab Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto
Colorectal cancer (CRC) develops by two major genetic pathways, characterized by microsatellite instability positive (MSI+) and microsatellite stable (MSS) tumor phenotypes. How the etiology of these two pathways is influenced by genetic and environmental risk factors is a major area of investigation. Striking differences exist regarding the mutational spectra, pathologic features and clinical prognosis between mismatch repair (MMR) deficient (MSI+) and proficient (MSS) tumors. Lifetime risk of colon cancer varies significantly based on the family history. Germline mutations of MMR genes including MLH1 cause a dominantly inherited cancer susceptibility syndrome, HNPCC, associated with MSI+ tumors, while hypermethylation of MLH1 accounts for the majority of sporadic MSI+ CRCs. Whether MLH1 hypermethylation contributes to familial CRC is largely unknown. Carcinogen susceptibility genes also interact with environmental and dietary risk factors; and functional polymorphisms in such genes may confer different risks to CRC patients with MSI+ and MSS tumor phenotypes. I will present data from our group addressing these research issues. Aim: 1) To determine the contribution of MLH1 promoter hypermethylation to colorectal tumorigenesis in HNPCC and familial CRC patients. 2) To determine the association of functional polymorphism C677T in the MTHFR carcinogen susceptibility gene and to examine interactions between allelic variants and related environmental risk factors in the MSI+ versus MSS colon tumors. Methods: 1) Familial CRC patients (n=62) identified through a hospital-based registry were stratified into distinct groups of familial risk based on clinical and molecular criteria including tumor MSI status and germline MMR gene mutation status. MLH1 promoter hypermethylation was analyzed by methylation specific PCR and by high throughput MethyLight assay. 2) Incident CRC cases were identified through a population-based registry (OFCCR) and their epidemiologic data including diet and family history was obtained. MTHFR C677T frequency was determined in over 800 CRC cases stratified according to their tumor MSI status. Polymorphism frequency was analyzed by chi square test of association and interaction between genetic variant and associated risk factors including age at diagnosis and sex of the patient, vitamins, alcohol intake and folate was investigated by multivariate analyses. Results and conclusions: A small subset (<10%) of confirmed HNPCC cases harbored MLH1 promoter hypermethylation. Upto 40% of familial CRC cases without a detectable germline MMR mutation showed MLH1 hypermethylation and a trend towards late age of onset. MTHFR C677T was not associated with tumor MSI status, but maybe related to family history. Results of interaction between MTHFR C677T and associated risk factors will be presented.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 996 (Genetic & environmental interactions).