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Expression levels of many genes are altered in colon cancer, relative to normal colonic mucosa. We recently reported that such differences also exist between grossly normal colonic mucosa of individuals with and without colon cancer, and between individuals with and without a family history of colon cancer. Here we report a study of individuals with no cancer but with polyps in the transverse, ascending/descending, or rectosigmoid colon.Biopsies of grossly normal-appearing colonic mucosa from the rectosigmoid colon were taken from individuals with polyps, with or without personal/family history of colon cancer, and gene expression profiles compared with those from biopsies of control patients, with no polyps or known personal/family history. A global expression analysis was conducted of the same 15 genes used in our previous studies.We found significant differences in gene expression in normal-appearing rectosigmoid colonic mucosa between individuals with polyps and controls, regardless of whether personal or family history of cancer was present.Alterations in gene expression patterns in morphologically normal-appearing colonic mucosa are associated with the presence of adenomatous polyps. Prospective studies will be required to determine whether these alterations in gene expression can be used to predict risk of developing colon cancer.