APC mutations are sufficient for the growth of early colorectal adenomas

It is not clear whether APC mutations are sufficient for early colorectal a denomas to grow or whether additional mutations at other loci are required. We previously have screened 210 early colorectal adenomas from familial ad enomatous polyposis patients for mutations and allelic loss at APC. Here, w e determined whether allelic loss at APC had any effect on the nearby alpha -catenin gene. However, loss on 5q in familial adenomatous polyposis adenom as rarely extended as far as alpha-catenin, and no differences in alpha-cat enin protein expression were found in tumors that showed loss encompassing both APC and alpha-catenin. We then screened all 210 tumors for mutations a t candidate loci other than APC (K-ras, beta-catenin, and allelic loss at 1 p33-p35 and 1p36) and for microsatellite instability (MSI). Each of these l oci has been implicated previously in early colorectal tumorigenesis. One t umor harbored a beta-catenin mutation and another MSI, but none showed K-ra s mutation or allelic loss at 1p33-p35 or 1p36. These data support. the fol lowing hypotheses derived from sporadic colorectal tumors: beta-catenin mut ations are generally an alternative to mutations at APC, MSI is not usually an early phenomenon in colorectal tumorigenesis, and K-ras mutations are m ore typical of large- and moderate-sized adenomas. Contrary to some previou s reports, chromosome 1p allelic loss is infrequent in very early adenomas. APC mutations are generally sufficient for colorectal tumors to grow to ab out 1-cm diameter, although chance mutations at other loci can provide thes e early colorectal adenomas with a selective advantage, and some colorectal tumors may develop along a pathway not involving APC.