Mutations of the APC gene in human sporadic colorectal cancers.
ABSTRACT Mutations of the APC gene are reported to occur frequently in sporadic colorectal adenomas and adenocarcinomas. We studied APC gene mutations in cases of human sporadic colorectal cancer in order to evaluate their correlation with pathologic characteristics and clinical prognosis.
Most of the mutations of the APC gene (95%) are nonsense or frame shift mutations, encoding for truncated APC proteins. For this reason, mutation detection of the APC gene was performed using the in vitro synthesized protein (IVSP) assay, analysing the region between nucleotide 2058 and nucleotide 5079 of the gene, containing the mutation cluster region.
Out of 58 cases of colorectal cancer, 29 presented a mutated form of APC (mutation frequency 50%). We did not find a statistically significant correlation between APC gene mutation and age, sex, localization of the primary tumour, grading, Crohn-like lymphoid reaction or presence of residual adenoma. Tumours with low invasivity (Dukes' stages A and B) were less frequently mutated (12/27, 44.5%) than tumours of Dukes' stage C (15 out of 21, 71.4%), which developed macroscopically secondary metastasis with variable latency after surgery. Highly invasive tumours with synchronous metastases (Dukes' stage D) had, instead, a low frequency of APC mutations (20%, 2/10) (P = 0.02, compared with Dukes' stages A, B and C). Conclusions: These data suggest that more aggressive Dukes' stage D tumours develop metastasis by means of an unknown mechanism, independent of APC mutation.
Article: Meat and fish consumption, APC gene mutations and hMLH1 expression in colon and rectal cancer: a prospective cohort study (The Netherlands).[show abstract] [hide abstract]
ABSTRACT: The aim of this study was to investigate the associations between meat and fish consumption and APC mutation status and hMLH1 expression in colon and rectal cancer. The associations were investigated in the Netherlands Cohort Study, and included 434 colon and 154 rectal cancer patients on whom case-cohort analyses (subcohort n = 2948) were performed. Total meat consumption was not associated with the endpoints studied. Meat product (i.e. processed meat) consumption showed a positive association with colon tumours harbouring a truncating APC mutation, whereas beef consumption was associated with an increased risk of colon tumours without a truncating APC mutation (incidence rate ratio (RR) highest versus lowest quartile of intake 1.61, 95% confidence interval (CI) 0.96-2.71, p-trend = 0.04 and 1.58, 95% CI 1.10-2.25, p-trend = 0.01, respectively). Consumption of other meat (horsemeat, lamb, mutton, frankfurters and deep-fried meat rolls) was associated with an increased risk of rectal cancer without a truncating APC mutation (RR intake versus no intake 1.79, 95% CI 1.10-2.90). No associations were observed for meat consumption and tumours lacking hMLH1 expression. Our data indicate that several types of meat may contribute differently to the aetiology of colon and rectal cancer, depending on APC mutation status but not hMLH1 expression of the tumour.Cancer Causes and Control 12/2005; 16(9):1041-54. · 2.88 Impact Factor
Article: Genetic models of human cancer as a multistep process. Paradigm models of colorectal cancer, breast cancer, and chronic myelogenous and acute lymphoblastic leukaemia.[show abstract] [hide abstract]
ABSTRACT: Tumour formations arise as a consequence of alterations in the control of cell proliferation as well as with disorders in interactions between cells and their environment that result in invasion and metastasis. Recent advances in understanding the genetic basis of malignant diseases have been dominated by research in colorectal cancer. Genetic alterations of several proto-oncogenes and tumor-suppressor genes (e.g. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes), as well as other genomic alterations, appear at characteristic stages of tumor development and are observed in most neoplasms. Generally, the normal cell has multiple independent mechanisms that regulate its growth and differentiation potential, and several separate events would, therefore, be needed to override these control mechanisms, as well as induce the other aspects of the transformed phenotype, like metastasis. These signals may be either positive or negative, and the acquisition of tumorigenicity results from genetic changes that affect these control points following a multistep mode. Statistics of the frequency of cancer incidence with age in humans indicate that for the genesis of e.g. lung carcinoma, five or six steps are required. Other types of cancers, such as leukemias and sarcomas, probably require quite a different number of rate-limiting changes. One of the best characterized tumours to provide a genetic model is colorectal tumorigenesis. Mutations implicated in breast cancer tumorigenicity are also studied and used as a genetic model in the literature worldwide. Finally, activation of c-abl in chronic myelogenous leukaemia (CML) and acute lymphoblastic leukaemia could also be presented as an example, which provides probably the strongest evidence for the role of proto-oncogenes in human malignancy process.Journal of experimental & clinical cancer research: CR 12/2005; 24(4):505-14. · 1.50 Impact Factor