Mutations in APC, CTNNB1 and K-ras genes and expression of hMLH1 in sporadic colorectal carcinomas from the Netherlands Cohort Study

BACKGROUND: The early to intermediate stages of the majority of colorectal tumours are thought to be driven by aberrations in the Wnt (APC, CTNNB1) and Ras (K-ras) pathways. A smaller proportion of cancers shows mismatch repair deficiency. The aim of this study was to analyse the co-occurrence of these genetic alterations in relation to tumour and patient characteristics. METHODS: In a group of 656 unselected sporadic colorectal cancer patients, aberrations in the APC, K-ras, CTNNB1 genes, and expression of hMLH1 were investigated. Additionally, tumours were divided in groups based on molecular features and compared with respect to patient's age at diagnosis, sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and differentiation. RESULTS: Mutations at the phosphorylation sites (codons 31, 33, 37, and 45) in the CTNNB1 gene were observed in tumours from only 5/464 patients. Tumours with truncating APC mutations and activating K-ras mutations in codons 12 and 13 occurred at similar frequencies (37% (245/656) and 36% (235/656), respectively). Seventeen percent of tumours harboured both an APC and a K-ras mutation (109/656). Nine percent of all tumours (58/656) lacked hMLH1 expression. Patients harbouring a tumour with absent hMLH1 expression were older, more often women, more often had proximal colon tumours that showed poorer differentiation when compared to patients harbouring tumours with an APC and/or K-ras mutation. CONCLUSION: CTNNB1 mutations seem to be of minor importance in sporadic colorectal cancer. The main differences in tumour and patient characteristics are found between groups of patients based on mismatch repair deficiency

Fruits, vegetables, and hMLH1 protein-deficient and -proficient colon cancer: The Netherlands cohort study.

BACKGROUND: Clinical and pathologic differences exist between colon carcinomas deficient and proficient in the mismatch repair protein hMLH1. Animal and in vitro studies suggest that fruits, vegetables, folate, and antioxidants are associated with colonic expression of mismatch repair genes. METHODS: Associations between consumption of fruits and vegetables and hMLH1 protein-deficient and -proficient colon cancer were evaluated in the Netherlands Cohort Study on diet and cancer using a case-cohort approach. A self-administered food frequency questionnaire was completed, in 1986, by 120,852 individuals ages 55 to 69 years. Using immunohistochemistry, hMLH1 protein expression was assessed in colon cancer tissue obtained from 441 patients who were identified over 7.3 years of follow-up excluding the initial 2.3 years. Incidence rate ratios (RR) were estimated for hMLH1 protein-deficient and -proficient colon cancer. RESULTS: hMLH1 protein expression was absent in 54 tumors (12.2%) and present in 387 tumors. Fruit consumption was associated with hMLH1 protein-deficient colon cancer [highest versus lowest tertile, RR, 0.46; 95% confidence interval (95% CI), 0.23-0.90; P(trend) = 0.029] but not with hMLH1 protein-proficient tumors (highest versus lowest tertile, RR, 1.03; 95% CI, 0.78-1.35; P(trend) = 0.81). Total consumption of vegetables was not associated with either type of tumor (hMLH1 protein deficient: RR, 0.86; 95% CI, 0.45-1.65; P(trend) = 0.67; hMLH1 protein proficient: RR, 0.94; 95% CI, 0.72-1.23; P(trend) = 0.72). No associations were observed for folate, fiber, antioxidants, or subgroups of vegetables. CONCLUSION: These analyses indicate that an inverse association between consumption of fruits and colon cancer may be confined to the subgroup of tumors with a deficient mismatch repair system