Molecular Differences between Sporadic Serrated and Conventional Colorectal Adenomas

Abstract

Purpose:The purpose is to compare the molecular characteristics of serrated adenomas (SAs) with those of conventional adenomas (CADs) and hyperplastic polyps (HPs).Experimental Design: We evaluated the proliferative activity and molecular alterations in 47 SAs (25 pure-type and 22 mixed-type), 71 CADs, and 23 HPs.Results: The proliferative activity of SAs, as evaluated by Ki-67 expression, was intermediate between CADs and HPs. There was no significant difference in the incidence of KRAS or p53 mutations between the three histological groups. In the microsatellite instability (MSI) analysis, 21% of SAs (9 of 43) showed MSI at two or more loci (MSI-H); corresponding values were 5% of CADs (3 of 64) and 8% of HPs (1 of 13; SAs versus CADs, P ‫؍‬ 0.0125). MSI-H was more likely to be found in pure-type SAs (36%; 8 of 22) than in mixed-type SAs (5%; 1 of 21; P ‫؍‬ 0.0212). Loss of hMLH-1 expression was found in 8 of 9 SAs with MSI-H. The incidence of BRAF or KRAS mutations was 36 and 15% of SAs, respectively; the combined incidence of BRAF and KRAS mutations occurred in 49% of SAs. However, there was no significant difference in the incidence of BRAF or KRAS mutations between SAs with and without MSI-H.Conclusions: Genetic instability is more frequently implicated in the tumorigenesis of SAs, especially pure-type SAs, than in that of CADs. In contrast, activation of the Ras/Raf/MEK/MAP kinase cascade by BRAF or KRAS mutation, independently of the genetic instability, may be associated with the progression of about half of SAs.

Differences in the histological findings, phenotypic marker expressions and genetic alterations between adenocarcinoma of the gastric cardia and distal stomach

“…Tissues were precisely microdissected under microscopic visualization using a PixCell laser capture microdissection system (Arcus Engineering, Mountain View, CA, USA) to avoid DNA contamination with that of inflammatory or stromal cell nuclei. Genomic DNA was extracted from the microdissected tissue as described previously (Konishi et al, 2004).…”

“…Mutations were detected by electrophoresis using a 3100 Genetic Analyzer (Applied Biosystems, CA, USA). The peak pattern was analysed using the QUISCA software (Konishi et al, 2004;Yamazaki et al, 2006). The nucleotide sequences of the DNA fragments with shifted peaks were determined using the Genetic Analyzer 310 with a BigDye Terminator (Applied Biosystems).…”

“…The primers and PCR conditions have been described elsewhere (Konishi et al, 2004;Yamazaki et al, 2006). The samples were subjected to capillary electrophoresis on an ABI 3100 Genetic Analyzer using the Genescan Analysis software (Applied Biosystems).…”

Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer

“…However, clonal genetic changes-including mutations of KRAS and BRAF and microsatellite instability-have been demonstrated in hyperplastic polyps. 11,15,18,19,[22][23][24] These lesions have been associated with an increased risk of malignancy in the hyperplastic polyposis syndrome, but may signify an increased risk of colorectal cancer also in other individuals. 18,22 In HNPCC as well as in familial colorectal cancer, a strong correlation has been found between adenomas and hyperplastic polyps, suggesting similar mechanisms for their initiation.…”

“…Consequently, a microsatellite instability-high phenotype has been reported in 0-4% of sporadic adenomas compared to 15-20% of sporadic carcinomas. [8][9][10][11] Whereas the mismatch repair defects in sporadic colorectal tumors are mainly associated with somatic hypermethylation of the MLH1 promoter, HNPCC tumors develop as a result of germline mutations in these genes. 7,12 Data on the frequency of microsatellite instability in HNPCC-associated adenomas are still quite scarce, but indicate that defective mismatch repair can be found in 24-93% of the adenomas.…”