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) alle les, predispose to only a few colon polyps(5). This leads to the hypot hesis 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 l ead 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. Screen ing of tumours from APC(AP) carriers revealed a reduction of LOH compa red with that of an unselected group of polyposis patients(7). In fact , no loss of the inherited APC(N) allele was observed, although sequen cing showed that the inherited APC(N) allele had frequently undergone point mutations and small deletions in the tumours. A low frequency lo ss of the inherited APC(AP) allele was seen. These findings support th e suggestion that the APC(AP) allele has residual gene activity and th at this activity modulates the spectrum and frequency of mutations tha t lead to adenoma formation.