Identification of FAP Locus Genes from Chromosome 5q21

Abstract

Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers, particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this locus, a portion of the region that is tightly linked to FAP was cloned. Six contiguous stretches of sequence (contigs) containing approximately 5.5 Mb of DNA were isolated. Subclones from these contigs were used to identify and position six genes, all of which were expressed in normal colonic mucosa. Two of these genes (APC and MCC) are likely to contribute to colorectal tumorigenesis. The MCC gene had previously been identified by virtue of its mutation in human colorectal tumors. The APC gene was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein. These two closely spaced genes encode proteins predicted to contain coiled-coil regions. Both genes were also expressed in a wide variety of tissues. Further studies of MCC and APC and their potential interaction should prove useful for understanding colorectal neoplasia.

Mouse models for colorectal cancer

“…FAP patients also display extracolonic manifestations, such as congenital hypertrophy of the retinal pigment epithelium, osteomas, medulloblastomas and desmoid tumors of the skin. The gene responsible for FAP has been identi®ed Joslyn et al, 1991;Kinzler et al, 1991). The gene, designated adenomatous polyposis coli (APC), is located on human chromosome 5.…”

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

“…This began with the identification of the adenomatous polyposis coli gene ( APC ) 2, in which germline mutations cause familial adenomatous polyposis (FAP), followed by the discovery of other genes such as MSH2 in Lynch syndrome 3 and mutY homologue ( MUTYH ) in MUTYH ‐associated polyposis (MAP) 4 (also called MYH‐associated polyposis). Germline variants in the genes LKB1 , SMAD4 , GREM1 , PTEN , BMPR1A and AXIN2 have also been implicated in predisposition to colorectal cancer and highlight a role for many pathways in tumourigenesis of the colon 5.…”

Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

“…The adenomatous polyposis coli (Apc) gene is mutated in up to 80% of sporadic colorectal cancers and is thought to be the key initiating event (Kinzler et al, 1991;Bienz and Clevers, 2000). The predominant role of Apc gene as a tumour suppressor is as a negative regulator of the Wnt signalling pathway.…”