Alleles of APC modulate the frequency and classes of mutations that read to colon polyps

Most inherited mutant alleles of the adenomatosis polyposis coli gene (APC) cause the appearance of large numbers of colon polyps(1-4), the familial polyposis syndrome. (These mutant alleles are designated APC(p) alleles.) A subset of APC mutations, the attenuated or APC(AP) alleles, predispose to only a few colon polyps(5). This leads to the hypothesis that if mutation of the inherited normal allele is rate limiting in polyp development, the increased number of polyps associated with the APC(p) allele indicates that the frequency of mutations that can lead to polyp formation is higher among APC(p) carriers than among APC(AP) carriers. We have previously suggested that the APC protein might modulate the frequency of mutations, such as loss of heterozygosity(6) (LOH), necessary for colon polyp formation(5). We thus reasoned that tumours from patients who carry an APC(AP) allele might show a reduced frequency of LOH compared with tumours from patients who carry an APC(p) allele. Loss of AAPC mutant alleles is designated as LOHAP. Screening of tumours from APC(AP) carriers revealed a reduction of LOH compared with that of an unselected group of polyposis patients(7). In fact, no loss of the inherited APC(N) allele was observed, although sequencing showed that the inherited APC(N) allele had frequently undergone point mutations and small deletions in the tumours. A low frequency loss of the inherited APC(AP) allele was seen. These findings support the suggestion that the APC(AP) allele has residual gene activity and that this activity modulates the spectrum and frequency of mutations that lead to adenoma formation.