Precancer: Mutant clones in normal epithelium outcompete and eliminate esophageal micro-tumors

Human epithelial tissues accumulate cancer-driver mutations with age1-7, yet tumor formation remains rare. The positive selection of these mutations argues they alter the behavior and fitness of proliferating cells8-10. Hence, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less-competitive neighbors9-12. However, little is known about how such dynamic competition in normal epithelia impacts early tumorigenesis. Here we show that the majority of newly formed esophageal tumors are eliminated through competition with mutant clones in the surrounding normal epithelium. We followed the fate of microscopic tumors in a mouse model of esophageal carcinogenesis. Most neoplasms are rapidly lost despite no indication of tumor cell death, decreased proliferation, or an anti-tumor immune response. Deep-sequencing of 10-day and 1-year-old tumors shows evidence of genetic selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased tumor removal, while pharmacologically inhibiting clonal competition reduced tumor loss. The results are consistent with a model where survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the adjacent normal tissue. We have identified an unexpected anti-tumorigenic role for mutant clones in normal epithelium by purging early neoplasms through cell competition, thereby preserving tissue integrity.

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A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing

Nature Communications ◽

10.1038/s41467-021-26788-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sanju Sinha ◽

Karina Barbosa ◽

Kuoyuan Cheng ◽

Mark D. M. Leiserson ◽

Prashant Jain ◽

...

Keyword(s):

Genome Editing ◽

Cell Types ◽

Selective Advantage ◽

Driver Mutations ◽

Cancer Driver ◽

Oncogenic Mutation ◽

Genome Wide ◽

Selection For ◽

Mutant Cells ◽

Selection Of

AbstractRecent studies have reported that genome editing by CRISPR–Cas9 induces a DNA damage response mediated by p53 in primary cells hampering their growth. This could lead to a selection of cells with pre-existing p53 mutations. In this study, employing an integrated computational and experimental framework, we systematically investigated the possibility of selection of additional cancer driver mutations during CRISPR-Cas9 gene editing. We first confirm the previous findings of the selection for pre-existing p53 mutations by CRISPR-Cas9. We next demonstrate that similar to p53, wildtype KRAS may also hamper the growth of Cas9-edited cells, potentially conferring a selective advantage to pre-existing KRAS-mutant cells. These selective effects are widespread, extending across cell-types and methods of CRISPR-Cas9 delivery and the strength of selection depends on the sgRNA sequence and the gene being edited. The selection for pre-existing p53 or KRAS mutations may confound CRISPR-Cas9 screens in cancer cells and more importantly, calls for monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing p53 and KRAS mutations.

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A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing

10.21203/rs.3.rs-199044/v1 ◽

2021 ◽

Author(s):

Sanju Sinha ◽

Karina Guerra ◽

Kuoyuan Cheng ◽

Mark Leiserson ◽

Prashant Jain ◽

...

Keyword(s):

Genome Editing ◽

Cell Types ◽

Selective Advantage ◽

Driver Mutations ◽

Cancer Driver ◽

Oncogenic Mutation ◽

Genome Wide ◽

Selection For ◽

Mutant Cells ◽

Selection Of

Abstract Recent studies have reported that genome editing by CRISPR–Cas9 induces a DNA damage response mediated by p53 in primary cells hampering their growth. This could lead to a selection of cells with pre-existing p53 mutations. In this study, employing an integrated computational and experimental framework, we systematically investigated the possibility of selection of additional cancer driver mutations during CRISPR-Cas9 gene editing. We first confirm the previous findings of the selection for pre-existing p53 mutations by CRISPR-Cas9. We next demonstrate that similar to p53, wildtype KRAS may also hamper the growth of Cas9-edited cells, potentially conferring a selective advantage to pre-existing KRAS-mutant cells. These selective effects are widespread, extending across cell-types and methods of CRISPR-Cas9 delivery and the strength of selection depends on the sgRNA sequence and the gene being edited. The selection for pre-existing p53 or KRAS mutations may confound CRISPR-Cas9 screens in cancer cells and more importantly, calls for monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing p53 and KRAS mutations.

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Genetic selection of sox1GFP-expressing neural precursors removes residual tumorigenic pluripotent stem cells and attenuates tumor formation after transplantation

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2006.03841.x ◽

2006 ◽

Vol 97 (5) ◽

pp. 1467-1480 ◽

Cited By ~ 113

Author(s):

S. Chung ◽

B.-S. Shin ◽

E. Hedlund ◽

J. Pruszak ◽

A. Ferree ◽

...

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Genetic Selection ◽

Tumor Formation ◽

Neural Precursors ◽

Selection Of

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The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin

Annals of Oncology ◽

10.1016/j.annonc.2020.11.023 ◽

2020 ◽

Author(s):

B. Hernando ◽

M. Dietzen ◽

G. Parra ◽

M. Gil-Barrachina ◽

G. Pitarch ◽

...

Keyword(s):

Normal Skin ◽

Driver Mutations ◽

Cancer Driver ◽

Effect Of Age ◽

Selection Of

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Prediction of meat quality traits in the abattoir using portable near-infrared spectrometers: heritability of predicted traits and genetic correlations with laboratory-measured traits

Journal of Animal Science and Biotechnology ◽

10.1186/s40104-021-00555-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Simone Savoia ◽

Andrea Albera ◽

Alberto Brugiapaglia ◽

Liliana Di Stasio ◽

Alessio Cecchinato ◽

...

Keyword(s):

Meat Quality ◽

Near Infrared ◽

External Validation ◽

Genetic Correlations ◽

Genetic Selection ◽

Quality Traits ◽

Eye Muscle ◽

Meat Quality Traits ◽

Color Traits ◽

Selection Of

Abstract Background The possibility of assessing meat quality traits over the meat chain is strongly limited, especially in the context of selective breeding which requires a large number of phenotypes. The main objective of this study was to investigate the suitability of portable infrared spectrometers for phenotyping beef cattle aiming to genetically improving the quality of their meat. Meat quality traits (pH, color, water holding capacity, tenderness) were appraised on rib eye muscle samples of 1,327 Piemontese young bulls using traditional (i.e., reference/gold standard) laboratory analyses; the same traits were also predicted from spectra acquired at the abattoir on the intact muscle surface of the same animals 1 d after slaughtering. Genetic parameters were estimated for both laboratory measures of meat quality traits and their spectra-based predictions. Results The prediction performances of the calibration equations, assessed through external validation, were satisfactory for color traits (R2 from 0.52 to 0.80), low for pH and purge losses (R2 around 0.30), and very poor for cooking losses and tenderness (R2 below 0.20). Except for lightness and purge losses, the heritability estimates of most of the predicted traits were lower than those of the measured traits while the genetic correlations between measured and predicted traits were high (average value 0.81). Conclusions Results showed that NIRS predictions of color traits, pH, and purge losses could be used as indicator traits for the indirect genetic selection of the reference quality phenotypes. Results for cooking losses were less effective, while the NIR predictions of tenderness were affected by a relatively high uncertainty of estimate. Overall, genetic selection of some meat quality traits, whose direct phenotyping is difficult, can benefit of the application of infrared spectrometers technology.

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Prescreening in large populations as a tool for identifying elevated CO2-responsive genotypes in plants

Functional Plant Biology ◽

10.1071/fp18087 ◽

2019 ◽

Vol 46 (1) ◽

pp. 1 ◽

Cited By ~ 5

Author(s):

Hiroyuki Shimono ◽

Graham Farquhar ◽

Matthew Brookhouse ◽

Florian A. Busch ◽

Anthony O'Grady ◽

...

Keyword(s):

Genetic Selection ◽

Co2 Concentration ◽

Elevated Atmospheric Co2 ◽

High Performing ◽

Active Selection ◽

Wide Range ◽

Large Populations ◽

Increase Productivity ◽

The Cost ◽

Selection Of

Elevated atmospheric CO2 concentration (e[CO2]) can stimulate the photosynthesis and productivity of C3 species including food and forest crops. Intraspecific variation in responsiveness to e[CO2] can be exploited to increase productivity under e[CO2]. However, active selection of genotypes to increase productivity under e[CO2] is rarely performed across a wide range of germplasm, because of constraints of space and the cost of CO2 fumigation facilities. If we are to capitalise on recent advances in whole genome sequencing, approaches are required to help overcome these issues of space and cost. Here, we discuss the advantage of applying prescreening as a tool in large genome×e[CO2] experiments, where a surrogate for e[CO2] was used to select cultivars for more detailed analysis under e[CO2] conditions. We discuss why phenotypic prescreening in population-wide screening for e[CO2] responsiveness is necessary, what approaches could be used for prescreening for e[CO2] responsiveness, and how the data can be used to improve genetic selection of high-performing cultivars. We do this within the framework of understanding the strengths and limitations of genotype–phenotype mapping.

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Biological control of tick populations: review and reflections

Cadernos de Saúde Pública ◽

10.1590/s0102-311x1994000100005 ◽

1994 ◽

Vol 10 (1) ◽

pp. 47-52 ◽

Cited By ~ 4

Author(s):

Norma V. Labarthe

Keyword(s):

Biological Control ◽

Genetic Selection ◽

Effective Vaccine ◽

Control Methods ◽

The Relationship ◽

Selection Of

This study is concerned with aspects of the relationship between ticks and their hosts that have a bearing on biological control of tick populations. It proposes control methods based on a program that would combine development of an effective vaccine with genetic selection of hosts.

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Genetic selection of lambda phage clones from a gene clonotheque

MGG Molecular & General Genetics ◽

10.1007/bf00333972 ◽

1986 ◽

Vol 203 (2) ◽

pp. 312-315

Author(s):

Anatolij A. Melnikov ◽

Istvan Fodor

Keyword(s):

Genetic Selection ◽

Lambda Phage ◽

Selection Of

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Nucleotide excision repair is impaired by binding of transcription factors to DNA

10.1101/028886 ◽

2015 ◽

Author(s):

Radhakrishnan Sabarinathan ◽

Loris Mularoni ◽

Jordi Deu-Pons ◽

Abel Gonzalez-Perez ◽

Nuria Lopez-Bigas

Keyword(s):

Nucleotide Excision Repair ◽

Mutation Rate ◽

Binding Sites ◽

Somatic Mutations ◽

Excision Repair ◽

Replication Timing ◽

Driver Mutations ◽

Cancer Driver ◽

Nucleotide Excision ◽

Active Transcription

Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears in great variability across the genome due to chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally, such as DNA-binding proteins, are unknown. Here we demonstrate that the rate of somatic mutations in melanoma tumors is highly increased at active Transcription Factor binding sites (TFBS) and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Therefore, our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of mutations at their binding sites. This finding has important implications in our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

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