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. 2000 Nov;53(11):841–845. doi: 10.1136/jcp.53.11.841

Pathogenesis of non-familial colorectal carcinomas with high microsatellite instability

K Shitoh 1, F Konishi 1, M Miyaki 1, T Iijima 1, T Furukawa 1, T Tsukamoto 1, H Nagai 1
PMCID: PMC1731121  PMID: 11127266

Abstract

Aims—Microsatellite instability (MSI) was first observed in hereditary non-polyposis colorectal carcinoma (HNPCC) and was subsequently seen in non-familial colorectal carcinoma. The relation between MSI and cancer associated genes in non-familial colorectal carcinomas has yet to be evaluated. To clarify this matter, changes in cancer associated genes were examined in non-familial colorectal carcinomas.

Methods—Alterations in the adenomatous polyposis coli (APC), p53, and Ki-ras genes were analysed in 24 MSI high (alterations in four to seven of seven loci), nine MSI low (alterations in one to three of seven loci), and 31 MSI negative non-familial carcinomas. The hMSH2 and hMLH1 genes were also analysed in 24 MSI high carcinomas.

Results—Both the frequencies and types of alterations in the APC and p53 genes in MSI high carcinomas were the same as those in MSI low and MSI negative carcinomas; however, they were different from those seen in HNPCC. The frequency of Ki-ras mutation was significantly lower in the MSI high cases (two of 24; 8%) than in the others (15 of 38; 39%). Somatic mutation of hMSH2 or hMLH1 was detected in six of 24 (25%) of the MSI high cases.

Conclusions—These results suggest that APC and p53 alterations occur irrespective of microsatellite instability status in non-familial colorectal carcinomas, and that Ki-ras mutation is not involved in MSI high non-familial colorectal carcinoma. The pathogenesis of these carcinomas may differ from both the usual adenoma–carcinoma sequence and HNPCC carcinogenesis.

Key Words: microsatellite instability • non-familial colorectal carcinoma • cancer associated genes

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Figure 1 MSI negative and positive cases determined using the BAT-26, Mfd26, and TP53 microsatellite markers. N, normal sample; Ca, carcinoma sample; MSI-, MSI negative; MSI+, MSI positive.

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Figure 2 DNA sequencing of the APC (adenomatous polyposis coli), p53, and Ki-ras genes. Sequencing of DNA fragments eluted from normal and mutant bands. (A) In number 125, 5 bp (GAAAA) are deleted at codon 1309 in exon 15 of the APC gene. (B) In number 112, A is replaced by T at codon 208 in exon 6 of the p53 gene (amino acid changed from Asp to Val). (C) In number 108, G is replaced by T at codon 12 in exon 1 of the Ki-ras gene (amino acid changed from Gly to Val).

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