Mutations of the adenomatous polyposis coli gene in familial polyposis coli patients and sporadic colorectal tumors.

We have isolated several genes in the chromosome 5q21 region tightly linked to hereditary familial polyposis coli (FAP) and Gardner's syndrome (GS). Two of these genes (MCC and APC) were found to be somatically altered by point mutation, deletion or insertion in tumors of sporadic colorectal cancer patients. One of them (adenomatous polyposis coli; APC) was also found to mutate in the germ-line of both APC and GS patients. The identification of these genes has significant implications for understanding the pathogenesis of colorectal neoplasia and for the diagnosis and counseling of individuals with inherited predispositions to colorectal cancer. Furthermore, in one colon carcinoma, we identified an interesting mechanism causing dysfunction of the APC gene. This gene was disrupted by a somatic insertion of a long interspersed repetitive element (LINE-1 sequence: L1) into the last exon. As an insertional sequence contains a 3' portion of the L1 consensus sequence including the poly(A) tract and an 8 bp target-site duplication was observed, this insertion is suspected to be caused by a retrotranscriptional insertion of one of the L1 sequences. This is the first case of the disruption of a tumor suppressor gene by the insertion of a movable genetic element.