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Somatic APC mutations in colorectal tumors from the EPIC-Norfolk prospective study of diet and cancer

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

1710 

There is growing epidemiological evidence to suggest that the large worldwide variation in the rates of colorectal cancer incidence can be attributed to differences in exposure to certain environmental factors and a ‘Westernized’ style of diet. Established environmental risk factors for colorectal neoplasia include high red and processed meat consumption, smoking and alcohol consumption (1).

The current model of colorectal carcinogenesis proposes that mutations in the tumor suppressor gene Adenomatous Polyposis Coli (APC) are key to the initiation of the colorectal cancer pathway (2). The majority of somatic mutations in APC occur between codons 1286-1513, a region known as the Mutation Cluster Region (MCR). However, mutational hotspots have been observed just outside of this region (3).

Mutation analysis of the extended MCR from codons 1281 to 1554 was performed on colorectal tumor samples collected from participants of the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC), with the aim of relating mutations back to dietary and lifestyle information collected for each individual at the start of the study.

Genomic DNA was extracted from sections of formalin-fixed paraffin-embedded tumor tissue. The extended MCR was amplified via PCR in three overlapping fragments using a high-fidelity polymerase, and the resulting products were directly sequenced. Mutations were identified using the Genome Assembly Program (GAP4). A validation study prior to the analysis of EPIC samples showed good agreement between the DNA extracted from snap frozen and formalin fixed tissue.

In the initial set of EPIC tumor samples, approximately 50% carried a fixed mutation in the extended MCR with more than 90% of these resulting in a protein truncation. Approximately one-third of all mutations in the region occurred at codon 1554, which lies within a polyadenine tract (A6). This hotspot may represent microsatellite instability (MSI) due to a mutation in one of the genes responsible for DNA mismatch repair. Studies are underway to determine MSI status of tumours with a mutation at codon 1554.

1. Norat, T. et al. Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition. J Natl Cancer Inst 97, 906-16 (2005).

2. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759-67 (1990).

3. Rowan, A. J. et al. APC mutations in sporadic colorectal tumors: A mutational "hotspot" and interdependence of the "two hits". Proc Natl Acad Sci U S A 97, 3352-7 (2000).