Genetic heterogeneity in sporadic colorectal adenomas

Abstract

The majority of colorectal cancers develop from adenomatous polyps under the influence of factors that are still poorly understood. Tumourigenesis is generally considered a multistep process in which multiple genetic alterations occur, eventually reflected in abnormalities of the cellular DNA content. Macroscopical features such as tumour size and tumour architecture (tubular, tubulovillous, or villous) are correlated wit the chance of malignancy in the lesion. Grade of dysplasia can be considered an indicator for the level of progression of the adenoma towards invasive carcinoma. These characteristics were correlated with the presence or absence of K‐ras mutations and the DNA ploidy in a prospective study performed on 46 large sporadic colorectal adenomas resected by endoscopy. DNA ploidy and K‐ras mutations were analysed in two samples taken at distant sites in the adenomas. Aneuploidy was present in 12 adenomas (26 per cent) and K‐ras mutations occurred in 26 (57 per cent). A highly significant correlation was found between aneuploidy and adenoma size, architecture, and grade of dysplasia. The presence of K‐ras mutations was significantly correlated only with the size of the adenomas. The proportion of adenomas with aneuploidy and/or a K‐ras mutation increased when two samples were analysed instead of one. This observation suggests that the prevalence of genetic mutations and of aneuploidy is probably underestimated, as generally only one sample is investigated. No correlation was observed between K‐ras mutations and ploidy. This study demonstrates the presence of genetic heterogeneity in colorectal adenomas and supports the notion that K‐ras mutation is an early event, while aneuploidy is a late event in the adenoma–carcinoma sequence. © 1997 John Wiley & Sons, Ltd.

Associations of Ki-ras Proto-oncogene Mutation and p53 Gene Overexpression in Sporadic Colorectal Adenomas with Demographic and Clinicopathologic Characteristics

“…In addition, individuals with rectal adenomas were twice as likely to have Ki-ras mutations compared with those with distal colonic adenomas ( Table 2). Univariate analyses of the relationships among adenoma size, degree of dysplasia, histology, and Ki-ras mutation showed positive associations with point estimates similar to those reported in the literature (15)(16)(17)(18)(44)(45)(46)(47)(48)(49)(50)(51). However, because these characteristics are highly correlated, multivariate analysis was required to assess the independent effect of each and showed that the presence of tubulovillous histology (OR, 4.19; 95% CI, 2.62-6.68) or of villous histology (OR, 5.45; 95% CI, 2.28-13.03) was strongly related to Ki-ras mutation as compared with tubular adenomas.…”

“…Several smaller studies, generally using univariate analyses, have investigated the relationships among Ki-ras mutation and histology, size, and grade of dysplasia. Many, but not all, show a significant association between Ki-ras mutation and adenoma size (16,17,44,45) or more advanced histology (15,18,(46)(47)(48)(49)(50)(51)58). HGD has also been associated with Ki-ras mutation in some (17,44), but not all of these studies (16,19).…”

“…More than 50% of adenomas containing cancer (35) and 37% to 70% of cancers (19,26,37,39,40,45,53,56,(69)(70)(71)(72) have been found to have p53 overexpression. Interpretation of p53 immunohistochemistry is a common difficulty in generalizing studies and although the correlation with p53 mutation is far from perfect, p53 overexpression has been used as a surrogate for mutation in numerous studies (15, 19, 39, 40, 53, 55, 56, 68, 71).…”

Mutations associated with microsatellite unstable colorectal carcinomas exhibit widespread intratumoral heterogeneity

“…TP53 mutations have been reported to show intratumoral heterogeneity in intramucosal carcinomas but were homogeneous throughout invasive carcinomas (Kuwabara et al, 1998). Colorectal adenomas were also found to be heterogeneous for KRAS mutations and aneuploidy (Giaretti et al, 1996;Saraga et al, 1997). Thus, although mutational heterogeneity is present in several genes in microsatellite stable colorectal adenomas, it does not seem to be a common feature in carcinomas.…”

The Frequency of K-ras Mutation in Colorectal Adenocarcinomas with Absence of Distant Metastasis at Diagnosis

“…CRC development is a result of acquisition of multiple genetic changes such as mutations of tumor suppressor genes and various prooncogenes. In recent studies, K-ras mutations were detected in rate of 30% -50% in colorectal adenocarcinomas [2][3][4][5][6][7][8][9][10][11][12]. K-ras gene is located on chromosome 12 and encodes G protein showing GTPase activity [2].…”