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Modifier genes and familial adenomatous polyposis coli

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The number of adenomatous polyps in somebody with familial adenomatous polyposis (FAP) is influenced by the position of the germline mutation in the APC gene. This, however, does not explain the variability within families which is consistent with the effect of modifier genes. Such genes are known to affect disease severity in a mouse model. Several common polymorphisms may be associated with increased risk of colorectal cancer and could act as APC modifier genes. Researchers in London, UK have studied polymorphisms in eight genes (MTHFR, NAT1, NAT2, GSTM, GSTT, cyclin D1, E-cadherin, and APC) in relation to severity of FAP (number of polyps per colectomy specimen standardised for colon size).

DNA samples (from blood, established cell line, or fixed normal tissue) were obtained from 151 patients from 51 families with established classical FAP. The relationship between polyp count and genotype at each polymorphic site was assessed, making allowance for the position of the germline APC mutation. Among all 151 patients severe disease (high polyp count) was associated with variations in the N-acetyltransferase genes; more specifically with the absence of the NAT1*10 genotype and the presence of both NAT1*non-10 and NAT2*fast genotypes. There was a weak association between severe disease and the APCT1493C allele. None of the other polymorphisms analysed was associated with disease severity. Among patients with germline mutations in the “mutation cluster region” (MCR) severe disease was associated with the presence of NAT2*fast alleles.

Alleles at NAT1 and/or NAT2 loci on chromosome 8p22 may act as disease severity modifiers in patients with FAP and may explain a twofold variation in polyp number.