ACB-PCR Quantification of K-<i>RAS</i>Codon 12 GAT and GTT Mutant Fraction in Colon Tumor and Non-Tumor Tissue

Parsons, Barbara L.; Marchant-Miros, Kathryn E.; Delongchamp, Robert R.; Verkler, Tracie L.; Patterson, Tucker A.; McKinzie, Page B.; Kim, Lawrence T.

doi:10.1080/07357901003630975

Cited by 38 publications

(33 citation statements)

References 32 publications

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“…Furthermore, it was suggested that RAF inhibitors potentiate pre-existing mutations (potentially UV-induced) in keratinocytes, resulting in the progression of cancerous lesions early after RAF inhibitor therapy (Figure 1a) [59,60]. These findings highlight the importance of characterizing patient tumors for both BRAF and RAS activating mutations, and raise the possibility that molecularly targeted therapies may induce tumorigenesis in pre-existing RAS-mutated cells known to occur elsewhere in the body [61].…”

Section: Braf As a Therapeutic Targetmentioning

confidence: 92%

“…Dieterle et al [99] and Parsons et al [61] showed that only 27 and 14% of colon tumors, respectively, had levels of KRAS mutation detectable by DNA sequencing, while 51 or 78% of colon tumors had KRAS-mutant DNA fractions between 0.001% and 10%, respectively.…”

Section: Evidence That Tumor Subpopulations Are Impacting the Efficacmentioning

confidence: 97%

“…There is broad agreement that tumors are heterogeneous, and intratumoral genetic hetero geneity has been documented using many different techniques, including microdissection and DNA sequencing, whole genome amplification/single nucleus sequencing and ACB-PCR [61,[100][101][102]. Whether tumor heterogeneity exists at the time of tumor initiation remains a critical issue.…”

Section: Origins Of Tumor Heterogeneitymentioning

confidence: 99%

“…Bissell and Hines present evidence that normal tissue homeostasis can maintain clones of cells in a precancerous state [114]. ACB-PCR, a technique that measures the levels of specific point mutations within a DNA sample [115], has been used to show that KRAS-mutant cells are present in normal colonic mucosa (i.e., potentially precancerous cells) [61]. Furthermore, the idea that pre-existing, precancerous cells are held in check by normal tissue architecture and/or cell-cell communication may explain why BRAF inhibitors induce skin tumors (KA and cSCC) [51,[58][59][60].…”

Section: Origins Of Tumor Heterogeneitymentioning

confidence: 99%

“…With respect to colon cancer, it has been established that: undetected KRAS-mutant subpopulations are quite prevalent [61,99]; patients with KRAS wild-type tumors may show response when treated with a single molecularly targeted agent after which resistance and relapse may occur [18]; and KRAS mutation has been detected in some tumors (initially characterized as wild-type) following treatment and relapse [90]. These results suggest that when therapy targets the predominant clone within a tumor (non-KRAS mutant), the diminution or ablation of that clone probably provides an opportunity for therapy-resistant, minor subpopulations to flourish (Figure 1b).…”

Section: Tumor Heterogeneity As An Obstacle For Personalized Cancer Tmentioning

confidence: 99%

See 4 more Smart Citations

Hotspot oncomutations: implications for personalized cancer treatment

Myers

Wang

McKim

et al. 2012

Expert Review of Molecular Diagnostics

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Understanding the extent to which specific tumor mutations impact or mediate patient response to particular cancer therapies has become a rapidly increasing area of research. Recent research findings regarding four predominant mutational targets (KRAS, BRAF, EGFR and PIK3CA) show that these tumor mutations have predictive power for identifying which patients are likely to respond to particular therapies, and have prognostic significance irrespective of treatment. However, in this regard, the literature is frequently nuanced and sometimes contradictory. This lack of clarity may be due, at least in part, to the utilization of mutation detection methods with varying sensitivities across studies of different patient populations. Nevertheless, considerable evidence suggests minor tumor subpopulations may be contributing to inappropriate patient stratification, development of resistance to treatment, and the relapse that often follows treatment with molecularly targeted therapies. Consequently, mutant tumor subpopulations need to be considered in order to improve strategies for personalized cancer treatment.

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Section: Braf As a Therapeutic Targetmentioning

confidence: 92%

Section: Evidence That Tumor Subpopulations Are Impacting the Efficacmentioning

confidence: 97%

Section: Origins Of Tumor Heterogeneitymentioning

confidence: 99%

Section: Origins Of Tumor Heterogeneitymentioning

confidence: 99%

Section: Tumor Heterogeneity As An Obstacle For Personalized Cancer Tmentioning

confidence: 99%

See 3 more Smart Citations

Hotspot oncomutations: implications for personalized cancer treatment

Myers

Wang

McKim

et al. 2012

Expert Review of Molecular Diagnostics

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show abstract

Oncomutations as biomarkers of cancer risk

Parsons

Myers

Meng

et al. 2010

Environ and Mol Mutagen

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Cancer risk assessment impacts a range of societal needs, from the regulation of chemicals to achieving the best possible human health outcomes. Because oncogene and tumor suppressor gene mutations are necessary for the development of cancer, such mutations are ideal biomarkers to use in cancer risk assessment. Consequently, DNA-based methods to quantify particular tumor-associated hotspot point mutations (i.e., oncomutations) have been developed, including allele-specific competitive blocker-PCR (ACB-PCR). Several studies using ACB-PCR and model mutagens have demonstrated that significant induction of tumor-associated oncomutations are measureable at earlier time points than are used to score tumors in a bioassay. In the particular case of benzo[a]pyrene induction of K-Ras codon 12 TGT mutation in the A/J mouse lung, measurement of tumor-associated oncomutation was shown to be an earlier and more sensitive endpoint than tumor response. The measurement of oncomutation by ACB-PCR led to two unexpected findings. First, oncomutations are present in various tissues of control rodents and "normal" human colonic mucosa samples at relatively high frequencies. Approximately 60% of such samples (88/146) have mutant fractions (MFs) >10(-5), and some have MFs as high as 10(-3) or 10(-4). Second, preliminary data indicate that oncomutations are present frequently as subpopulations in tumors. These findings are integrated into a hypothesis that the predominant preexisting mutations in particular tissues may be useful as generic reporters of carcinogenesis. Future research opportunities using oncomutation as an endpoint are described, including rodent to human extrapolation, dose-response assessment, and personalized medicine.

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Genotoxicity testing: Moving beyond qualitative “screen and bin” approach towards characterization of dose‐response and thresholds

Pottenger¹,

Gollapudi²

2010

Environ and Mol Mutagen

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For more than 40+ years, genotoxicity data have been interpreted in a qualitative, binary mode; a chemical is considered either positive or negative for a response in the test system. Although dose-response information is sometimes used in this decision, it is not routine to obtain the amount of information needed to inform risk assessment, for example to determine no-observed-genotoxic-effect-levels, primarily due to the historical view of genotoxic responses as "linear, no-threshold." Only recently have researchers begun to address this issue through robust experimental designs and application of statistical models. A growing body-of-evidence supports the existence of response thresholds for a number of mutagenic agents, in vitro and in vivo. Clearly, simple observation of a "hockey-stick" dose-response curve is not sufficient to establish a threshold. Collection of robust empirical data must be supported with an analysis of biological plausibility for the observed threshold. In this context, a chemical-specific mode-of-action (MOA) approach, which identifies key events responsible for the observed mutagenic effect, is extremely valuable. Biomarkers of key events, providing qualitative and quantitative information, can be integrated in a weight-of-evidence-based assessment of genotoxicity data from multiple test systems and used to identify data gaps to resolve/reduce uncertainties during the risk assessment process. To this end, specific recommendations on study design and data analysis are proposed. As the Environmental Mutagen Society celebrates its 40th anniversary, the field of genetic toxicology is marking a milestone on the path to a new paradigm, using a MOA, data-driven approach to answer questions about thresholds for genotoxic agents.

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ACB-PCR Quantification of K-RASCodon 12 GAT and GTT Mutant Fraction in Colon Tumor and Non-Tumor Tissue

Cited by 38 publications

References 32 publications

Hotspot oncomutations: implications for personalized cancer treatment

Hotspot oncomutations: implications for personalized cancer treatment

Oncomutations as biomarkers of cancer risk

Genotoxicity testing: Moving beyond qualitative “screen and bin” approach towards characterization of dose‐response and thresholds

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