Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene

Abstract

We examined somatic mutations of the adenomatous polyposis coli (APC) gene in 63 colorectal tumors (16 adenomas and 47 carcinomas) developed in familial adenomatous polyposis (FAP) and non-FAP patients. In addition to loss of heterozygosity (LOH) at the APC locus in 30 tumors, 43 other somatic mutations were detected. Twenty-one of them were point mutations; 16 nonsense and two missense mutations, and three occurred in introns at the splicing site. Twenty-two tumors had frameshift mutations due to deletion or insertion; nineteen of them were deletions of one to 31 bp and three were a 1-bp insertion. One tumor had a 1-bp deletion in an intron near the splicing site. Hence, 41 (95%) of 43 mutations resulted in truncation of the APC protein. Over 60% of the somatic mutations in the APC gene were clustered within a small region of exon 15, designated as MCR (mutation cluster region), which accounted for less than 10% of the coding region. Combining these data and the results of LOH, more than 80% of tumors (14 adenomas and 39 carcinomas) had at least one mutation in the APC gene, of which more than 60% (9 adenomas and 23 carcinomas) had two mutations. These results strongly suggest that somatic mutations of the APC gene are associated with development of a great majority of colorectal tumors.

Genetic mutations in human rectal cancers detected by targeted sequencing

“…29 This exon also contains the mutation cluster region between codons 1286 and 1513, a region that contains 60%-90% of APC mutations. 6,30 Accordingly, 13/16 (81.3%) of the mutations identified in our study were within these codons.…”

Group IVA Cytosolic Phospholipase A2 Regulates the G2-to-M Transition by Modulating the Activity of Tumor Suppressor SIRT2

“…Indeed, we previously showed that deletion of cPLA 2 ␣ resulted in fewer and smaller tumors in APC Min mice (19,20). Aneuploidy is a significant feature of sporadic colorectal cancer, and the majority of such cancers carry APC mutations resulting in truncated APC proteins lacking the C terminus (48). It was shown that the C terminus of APC binds microtubules and stimulates polymerization of tubulin in vitro and in vivo (49,50).…”

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

“…Biallelic mutation of the APC gene occurs in 45%–80% of colorectal cancers [5–7] and is observed in the earliest detectable lesions [2]. The APC locus was originally identified based on its link to familial adenomatous polyposis coli (FAP), an inherited syndrome of cancer predisposition [8–11].…”

“…Mutations in APC are often frameshifts, insertions or deletions that introduce premature stop codons and lead to the production of a truncated APC protein. Amino acids 1000 to 1600 of APC have been identified as a mutation cluster region that represents roughly 20% of the total (2,843-amino acid) protein yet contains about 60% of all identified mutation sites [7]. The following sections detail functions of the wild-type APC protein, all of which are weakened or lost through the acquisition of pathogenic mutations.…”