Journal Article

Occurrence of H-<i>ras</i> codon 61 CAA to AAA mutation during mouse liver tumor progression

Barbara L. Parsons, Sandra J. Culp, Mugimane G. Manjanatha and Robert H. Heflich

in Carcinogenesis

Volume 23, issue 6, pages 943-948
Published in print June 2002 | ISSN: 0143-3334
Published online June 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.6.943
Occurrence of H-ras codon 61 CAA to AAA mutation during mouse liver tumor progression

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The initiating mutations of a tumor are present in each of the cancerous cells comprising the tumor. Identification and measurement of the subsequent mutations that occur during tumor progression, however, requires mutation detection in a smaller subset of the tumor cells. In this study, allele-specific competitive blocker PCR (ACB-PCR), a genotypic selection method with the sensitivity to detect a specific point mutation in the presence of a 105-fold excess of wild-type DNA sequence, was used to measure H-ras codon 61 CAA to AAA mutation in mouse liver tumors that did not have this mutation as an initiating event. Twenty-one spontaneous or chemically induced mouse liver tumors, negative for the H-ras codon 61 CAA to AAA mutation by DNA sequencing or denaturing gradient gel electrophoresis, were analyzed for this mutation by ACB-PCR. The mutation was detected at some level in 71% of these tumors. The mutation was detected in adenomas and carcinomas more frequently (13 of 14 tumors) and at significantly higher mutant fractions than it was detected in histiocytic sarcomas (1 of 5 tumors). These data indicate that the same oncogenic point mutation that can be identified as a tumor-initiating event based on its clonal amplification in a tumor can also be present in only a small sub-population of tumor cells where the mutation must have been fixed at a later stage in tumor development. The occurrence of a mutation as a primary or secondary event probably reflects the stochastic nature of mutation and is likely to be affected by the mutation rate for each target site.

Keywords: ACB-PCR, Allele specific competitive blocker PCR; bp, basepair, DGGE, denaturing gradient gel electrophoresis; PCR, polymerase chain reaction.

Journal Article.  4975 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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