Low-Frequency
            <i>Kras</i>
            Mutations are Prevalent in Lung Adenocarcinomas

Myers, Meagan B.; McKim, Karen L.; Meng, Fanxue; Parsons, Barbara L.

doi:10.2217/pme.14.69

Cited by 18 publications

(27 citation statements)

References 58 publications

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“…This was based on the assumption that an increase in cancer MF (relative to normal) would indicate that the mutation provided a positive selective advantage during tumor progression. ACB-PCR has been used to show significant increases in KRAS G12D or KRAS G12V mutation in colon, lung, and thyroid tumors as compared to normal tissues [20] , [21] , [22] . However, no significant differences in KRAS G12D and KRAS G12V MF were observed between DCs and normal breast.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, low frequency measurement of KRAS mutation in breast cancer is of interest, because minor KRAS mutant subpopulations (not detected by DNA sequencing) exist and have been shown to cause therapeutic resistance in other types of cancer [5] , [6] . Minor subpopulations of KRAS mutant cells (G12D and G12V), which exist in lung, thyroid, and colon cancers, have been quantified using Allele-specific Competitive Blocker PCR (ACB-PCR) [20] , [21] , [22] . Among PTCs, for example, 29% and 35% of cancers had mutant subpopulations of KRAS G12D and G12V, respectively, at levels greater than the upper 95% confidence interval of that present in normal thyroid, despite KRAS mutations being reported in only ~ 2% of PTCs by DNA sequencing [7] .…”

Section: Introductionmentioning

confidence: 99%

“…Among PTCs, for example, 29% and 35% of cancers had mutant subpopulations of KRAS G12D and G12V, respectively, at levels greater than the upper 95% confidence interval of that present in normal thyroid, despite KRAS mutations being reported in only ~ 2% of PTCs by DNA sequencing [7] . DNA sequencing has detected KRAS G12D and G12V mutations in 3% and 4% of lung adenocarcinomas, respectively, but ACB-PCR demonstrated that 76% of the lung adenocarcinomas had a KRAS G12D or G12V mutant fractions (MFs) greater than the upper 95% confidence interval of that measured in normal lung [20] . Similar findings of prevalent KRAS mutant subpopulations in colonic adenomas and/or carcinomas have been obtained using ACB-PCR and other sensitive mutation detection methods [5] , [22] .…”

Section: Introductionmentioning

confidence: 99%

“…ACB-PCR is an allele-specific PCR amplification method that can quantify specific base substitution mutations when the mutation is present at a level of at least three mutant copies per 300,000 wild-type (WT) copies of a gene sequence (MFs of ≥ 10 − 5 ) in a given DNA sample. ACB-PCR has been used to quantify levels of cancer driver mutations in normal tissues and corresponding cancer samples in order to elucidate the potential for spontaneous mutations in normal tissues to drive tumor development, and evaluate the potential for specific mutant cancer subpopulations to impact acquired resistance to treatment, [20] , [21] , [22] . Here we apply this paradigm to normal breast tissues and DCs of the breast, examining cancer driver mutations that are either frequently detected in DCs or have been implicated in responses to personalized cancer treatments in other cancer types.…”

Section: Introductionmentioning

confidence: 99%

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Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas

et al. 2016

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Mutant cancer subpopulations have the potential to derail durable patient responses to molecularly targeted cancer therapeutics, yet the prevalence and size of such subpopulations are largely unexplored. We employed the sensitive and quantitative Allele-specific Competitive Blocker PCR approach to characterize mutant cancer subpopulations in ductal carcinomas (DCs), examining five specific hotspot point mutations (PIK3CA H1047R, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E). As an approach to aid interpretation of the DC results, the mutations were also quantified in normal breast tissue. Overall, the mutations were prevalent in normal breast and DCs, with 9/9 DCs having measureable levels of at least three of the five mutations. HRAS G12D was significantly increased in DCs as compared to normal breast. The most frequent point mutation reported in DC by DNA sequencing, PIK3CA H1047R, was detected in all normal breast tissue and DC samples and was present at remarkably high levels (mutant fractions of 1.1 × 10− 3 to 4.6 × 10− 2) in 4/10 normal breast samples. In normal breast tissue samples, PIK3CA mutation levels were positively correlated with age. However, the PIK3CA H1047R mutant fraction distributions for normal breast tissues and DCs were similar. The results suggest PIK3CA H1047R mutant cells have a selective advantage in breast, contribute to breast cancer susceptibility, and drive tumor progression during breast carcinogenesis, even when present as only a subpopulation of tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas

et al. 2016

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“…ACB-PCR has been used to demonstrate that human tumors frequently possess subpopulations of KRAS mutant cells, which are not detected by DNA sequencing [36–39]. This indicates that KRAS mutation likely contributes to carcinogenesis to a greater extent than can be recognized by DNA sequence analyses.…”

Section: Introductionmentioning

confidence: 99%

Ovarian effects of prenatal exposure to benzo[a]pyrene: Roles of embryonic and maternal glutathione status

Luderer

Myers

Banda

et al. 2017

Reproductive Toxicology

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Females deficient in the glutamate cysteine ligase modifier subunit (Gclm) of the rate-limiting enzyme in glutathione synthesis are more sensitive to ovarian follicle depletion and tumorigenesis by prenatal benzo[a]pyrene (BaP) exposure than Gclm+/+ mice. We investigated effects of prenatal exposure to BaP on reproductive development and ovarian mutations in Kras, a commonly mutated gene in epithelial ovarian tumors. Pregnant mice were dosed from gestational day 6.5 through 15.5 with 2 mg/kg/day BaP or vehicle. Puberty onset occurred 5 days earlier in F1 daughters of all Gclm genotypes exposed to BaP compared to controls. Gclm+/− F1 daughters of Gclm+/− mothers and wildtype F1 daughters of wildtype mothers had similar depletion of ovarian follicles following prenatal exposure to BaP, suggesting that maternal Gclm genotype does not modify ovarian effects of prenatal BaP. We observed no BaP treatment or Gclm genotype related differences in ovarian Kras codon 12 mutations in F1 offspring.

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Variation in organ‐specific PIK3CA and KRAS mutant levels in normal human tissues correlates with mutation prevalence in corresponding carcinomas

Parsons

McKim

Myers

2017

Environ and Mol Mutagen

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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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Low-Frequency Kras Mutations are Prevalent in Lung Adenocarcinomas

Cited by 18 publications

References 58 publications

Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas

Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas

Ovarian effects of prenatal exposure to benzo[a]pyrene: Roles of embryonic and maternal glutathione status

Variation in organ‐specific PIK3CA and KRAS mutant levels in normal human tissues correlates with mutation prevalence in corresponding carcinomas

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