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Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses.

ABSTRACT: Mutations in oncogenes and tumor suppressor genes are responsible for tumorigenesis and represent favored therapeutic targets in oncology. We exploited homologous recombination to knock-in individual cancer mutations in the genome of nontransformed human cells. Sequential introduction of multiple mutations was also achieved, demonstrating the potential of this strategy to construct tumor progression models. Knock-in cells displayed allele-specific activation of signaling pathways and mutation-specific phenotypes different from those obtainable by ectopic oncogene expression. Profiling of a library of pharmacological agents on the mutated cells showed striking sensitivity or resistance phenotypes to pathway-targeted drugs, often matching those of tumor cells carrying equivalent cancer mutations. Thus, knock-in of single or multiple cancer alleles provides a pharmacogenomic platform for the rational design of targeted therapies.

SUBMITTER: Di Nicolantonio F

PROVIDER: S-EPMC2634925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Large-scale sequencing efforts have described the mutational complexity of individual cancers and identified mutations prevalent in different cancers. As a complementary approach, allele-specific competitive blocker PCR (ACB-PCR) is being used to quantify levels of hotspot cancer driver mutations (CDMs) with high sensitivity, to elucidate the tissue-specific properties of CDMs, their occurrence as tumor cell subpopulations, and their occurrence in normal tissues. Here we report measurements of PIK3CA H1047R mutant fraction (MF) in normal colonic mucosa, normal lung, colonic adenomas, colonic adenocarcinomas, and lung adenocarcinomas. We report PIK3CA E545K MF measurements in those tissues, as well as in normal breast, normal thyroid, mammary ductal carcinomas, and papillary thyroid carcinomas. We report KRAS G12D and G12V MF measurements in normal colon. These MF measurements were integrated with previously published ACB-PCR data on KRAS G12D, KRAS G12V, and PIK3CA H1047R. Analysis of these data revealed a correlation between the degree of interindividual variability in these mutations (as log10 MF standard deviation) in normal tissues and the frequencies with which the mutations are detected in carcinomas of the corresponding organs in the COSMIC database. This novel observation has important implications. It suggests that interindividual variability in mutation levels of normal tissues may be used as a metric to identify mutations with critical early roles in tissue-specific carcinogenesis. Additionally, it raises the possibility that personalized cancer therapeutics, developed to target specifically activated oncogenic products, might be repurposed as prophylactic therapies to reduce the accumulation of cells carrying CDMs and, thereby, reduce future cancer risk. Environ. Mol. Mutagen. 58:466-476, 2017. © 2017 This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

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Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses.

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