Carcinogenesis Advance Access published online on February 19, 2004
Carcinogenesis, doi:10.1093/carcin/bgh117
© 2004 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Epidemiology, University Maastricht, 6200 MD Maastricht, The Netherlands
Received 28 November 2003
; revised 22 January 2004
; accepted 6 February 2004
The adenomatous polyposis coli (APC) gene is considered to be a gatekeeper in colorectal tumourigenesis. Inactivating mutations in APC have been reported in 34-70% of sporadic colorectal cancer patients, the majority of which occur in the mutation cluster region (MCR). In this study, tumour tissue from 665 incident colorectal cancer patients, who originate from 120,852 men and women (55-69 years of age at baseline) participating in the Netherlands Cohort Study, was evaluated for the occurrence and type of APC mutations with regard to age at diagnosis, gender, family history of colorectal cancer, Dukes' stage, tumour differentiation and sub-localization. Mutation analysis of the MCR, which spans codons 1286-1513, was performed on archival adenocarcinoma samples using macrodissection, nested PCR and direct sequencing of purified PCR fragments. A large number of genetic aberrations (n=978), including point mutations (n=833), deletions (n=126) and insertions (n=19) was detected in the MCR in 72% of patients (479/665). In particular, we observed a large number of missense mutations, more than previously reported. This may indicate involvement in colorectal carcinogenesis, although their significance for APC functions is unclear. Truncating mutations were found in 37% of patients (248/665). Patients with rectosigmoid and rectum tumours relatively more frequently harboured C>T nonsense mutations and truncating frameshift mutations as compared to patients with proximal and distal colon tumours (P=0.009 and P=0.045, respectively). Differences in occurrence of truncating mutations with regard to tumour sub-localization suggest a different aetiology of tumourigenesis in colon and rectum.
APC mutations in sporadic colorectal carcinomas from the Netherlands cohort study
2 Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Pathology, University Maastricht, 6200 MD Maastricht, The Netherlands
3 Research Institute Growth and Development (GROW), Department of Pathology, University Maastricht, 6200 MD Maastricht, The Netherlands
4 TNO Nutrition and Food Research, 3700 AJ Zeist, The Netherlands
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