Somatic mutations of the APC, KRAS, and TP53 genes in nonpolypoid colorectal adenomas

Abstract

Colorectal adenomas are macroscopically visible morphological changes of the mucosa that can develop focal carcinoma in the absence of surgical intervention. The successive molecular changes proposed to occur at different stages in the adenoma-carcinoma sequence were primarily based on DNA studies of exophytic, polypoid-type adenomas. Not all colorectal lesions, however, display an exophytic phenotype and a presumed distinct colorectal neoplasm, the nonpolypoid adenoma, was subsequently described as a precursor of colorectal cancer. The low incidence of KRAS mutations in nonpolypoid colorectal adenomas reported previously suggested a different genetic basis for the transformation process in these lesions. We have pursued the identification of genetic changes in benign sporadic nonpolypoid colorectal adenomas in a selected Swedish patient group with no family history of colorectal cancer. Mutation screening of the adenomatous polyposis coli (APC), KRAS, and TP53 genes was conducted using the protein truncation test, heteroduplex-single-strand conformation polymorphism analysis, and denaturing gradient gel electrophoresis on PCR-amplified fragments. Fourteen mutations in the APC gene were characterized in 10/20 samples. Mutations in the KRAS and TP53 genes were identified in 3/57 and 4/51 adenomas, respectively. The mutation frequencies and distribution of mutations in APC correlate with published data on exophytic adenomas. The low mutation frequency of the TP53 gene is consistent with the benign nature of the research material. KRAS activation (an early event in polypoid colorectal adenomas) apparently does not play a significant role in nonpolypoid adenoma development but may result in the development of a polypoid configuration. Genes Chromosomes Cancer 27:202-208, 2000.

Genetic alterations in colorectal cancers with demethylation of insulin-like growth factor II

“…These results seemed counterintuitive considering that IGF2 activates both the RAS/RAF/MAP kinase and PIK3/AKT signaling pathways [1]. KRAS and BRAF gene mutations have been found with high frequencies in colorectal adenomas as advanced carcinomas, whereas PIK3CA mutation is rare in colorectal benign tumors; PI3K/AKT signaling may have a pivotal role in the malignant transformation of an adenoma [27,[53][54][55]. In fact, LOI was associated with an increased rate of tumor initiation rather than progression in a previous study using an IGF2 LOI mouse model [23], and we believe that IGF signaling might have an important role in driving the malignant potential of benign tumors in human colorectal tissue.…”

Familial adenomatous polyposis in two Black South African families

“…In a study by van Wyk et al. (22) on biopsies of flat adenoma of Swedish individuals, 50% of these cases had an APC mutation.…”

Colorectal neoplasia in ulcerative colitis—recent advances

“…Flat sporadic colorectal adenomas show some molecular differences (e.g. lower incidence of k‐ras mutations) from their more common polypoid counterparts, 87 and are thought more likely to progress to CRC 88 . If the latter also applies to UC‐related flat dysplasia, then a differential approach to managing DALMs and adenomas might have to be extended to flat dysplasia versus DALMs.…”