scholarly journals Mutation Vulnerability Characterizes Human Cancer Genes

2018 ◽  
Author(s):  
Yong Fuga Li ◽  
Fuxiao Xin
Keyword(s):  
Human Cancer ◽  
Hot Spot ◽  
Cancer Genes ◽  
Replication Errors ◽  
Somatic Evolution ◽  
Dna Mutations ◽  
Human Genes ◽  
Cancer Mutations ◽  
Random Patterns ◽  
Dna Replication Errors

AbstractRecent studies by Tomasetti et al. revealed that the risk disparity among different types of cancer is mainly determined by inherent patterns in DNA replication errors rather than environmental factors. In this study we reveal that inherent patterns of DNA mutations plays a similar role in cancer at the molecular level. Cancer results from stochastic DNA mutations, yet non-random patterns of cancer mutations emerge when we look across hundreds of cancer genomes. Over 500 cancer genes have been identified to date as the hot spot genes of cancer mutations. It is generally believed that these gene are mutated more frequently because they reside in functionally important pathways and are hence selected during the somatic evolution process of tumor progression. This theory however does not explain why many genes in the same pathways of cancer genes are not mutated in cancer. In this study, we challenge this view by showing that the inherent patterns of spontaneous mutations of human genes not only distinguish cancer causing genes and non-cancer genes but also shapes the mutation profile of cancer genes at the sub-gene level.

scholarly journals Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity

2015 ◽  
Vol 112 (19) ◽  
pp. E2467-E2476 ◽  
Author(s):  
Tony M. Mertz ◽  
Sushma Sharma ◽  
Andrei Chabes ◽  
Polina V. Shcherbakova
Keyword(s):  
Dna Synthesis ◽  
Human Cancer ◽  
Mutagenic Potential ◽  
Mutator Phenotype ◽  
Replication Errors ◽  
Intracellular Dntp ◽  
Mutator Effect ◽  
Dna Replication Errors

Defects in DNA polymerases δ (Polδ) and ε (Polε) cause hereditary colorectal cancer and have been implicated in the etiology of some sporadic colorectal and endometrial tumors. We previously reported that the yeast pol3-R696W allele mimicking a human cancer-associated variant, POLD1-R689W, causes a catastrophic increase in spontaneous mutagenesis. Here, we describe the mechanism of this extraordinary mutator effect. We found that the mutation rate increased synergistically when the R696W mutation was combined with defects in Polδ proofreading or mismatch repair, indicating that pathways correcting DNA replication errors are not compromised in pol3-R696W mutants. DNA synthesis by purified Polδ-R696W was error-prone, but not to the extent that could account for the unprecedented mutator phenotype of pol3-R696W strains. In a search for cellular factors that augment the mutagenic potential of Polδ-R696W, we discovered that pol3-R696W causes S-phase checkpoint-dependent elevation of dNTP pools. Abrogating this elevation by strategic mutations in dNTP metabolism genes eliminated the mutator effect of pol3-R696W, whereas restoration of high intracellular dNTP levels restored the mutator phenotype. Further, the use of dNTP concentrations present in pol3-R696W cells for in vitro DNA synthesis greatly decreased the fidelity of Polδ-R696W and produced a mutation spectrum strikingly similar to the spectrum observed in vivo. The results support a model in which (i) faulty synthesis by Polδ-R696W leads to a checkpoint-dependent increase in dNTP levels and (ii) this increase mediates the hypermutator effect of Polδ-R696W by facilitating the extension of mismatched primer termini it creates and by promoting further errors that continue to fuel the mutagenic pathway.

scholarly journals 3′ → 5′ Exonucleases of DNA Polymerases ϵ and δ Correct Base Analog Induced DNA Replication Errors on Opposite DNA Strands in Saccharomyces cerevisiae

Genetics ◽  
1996 ◽  
Vol 142 (3) ◽  
pp. 717-726 ◽  
Author(s):  
Polina V Shcherbakova ◽  
Youri I Pavlov
Keyword(s):  
Dna Replication ◽  
Dna Polymerases ◽  
Replication Errors ◽  
Dna Strands ◽  
Base Analog ◽  
Chromosome Iii ◽  
Dna Strand ◽  
Dna Replication Errors ◽  
Yeast Mutants ◽  
Lagging Strand

Abstract The base analog 6-N-hydroxylaminopurine (HAP) induces bidirectional GC → AT and AT → GC transitions that are enhanced in DNA polymerase ϵ and δ 3′ → 5′ exonuclease-deficient yeast mutants, pol2-4 and pol3-01, respectively. We have constructed a set of isogenic strains to determine whether the DNA polymerases δ and ϵ contribute equally to proofreading of replication errors provoked by HAP during leading and lagging strand DNA synthesis. Site-specific GC → AT and AT → GC transitions in a Pol→, pol2-4 or pol3-01 genetic background were scored as reversions of ura3 missense alleles. At each site, reversion was increased in only one proofreading-deficient mutant, either pol2-4 or pol3-01, depending on the DNA strand in which HAP incorporation presumably occurred. Measurement of the HAP-induced reversion frequency of the ura3 alleles placed into chromosome III near to the defined active replication origin ARS306 in two orientations indicated that DNA polymerases ϵ and δ correct HAP-induced DNA replication errors on opposite DNA strands.

scholarly journals Reduced survival in patients with stage-I non-small-cell lung cancer associated with DNA-replication errors

1997 ◽  
Vol 74 (3) ◽  
pp. 330-334 ◽  
Author(s):  
Rafael Rosell ◽  
Alex Pifarré ◽  
Mariano Monzó ◽  
Julio Astudillo ◽  
M. Paz López-Cabrerizo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Replication ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Stage I ◽  
Small Cell Lung ◽  
Replication Errors ◽  
Dna Replication Errors

scholarly journals Extrachromosomal DNA: An Emerging Hallmark in Human Cancer

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Sihan Wu ◽  
Vineet Bafna ◽  
Howard Y. Chang ◽  
Paul S. Mischel
Keyword(s):  
Human Cancer ◽  
Regulatory Elements ◽  
Annual Review ◽  
Publication Date ◽  
Cancer Evolution ◽  
Form And Function ◽  
Current State ◽  
Human Genes ◽  
Cancer Tumor ◽  
And Function

Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes and regulatory elements can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). ecDNA, because of its nonchromosomal inheritance, drives high-copy-number oncogene amplification and enables tumors to evolve their genomes rapidly. Furthermore, the circular ecDNA architecture fundamentally alters gene regulation and transcription, and the higher-order organization of ecDNA contributes to tumor pathogenesis. Consequently, patients whose cancers harbor ecDNA have significantly shorter survival. Although ecDNA was first observed more than 50 years ago, its critical importance has only recently come to light. In this review, we discuss the current state of understanding of how ecDNAs form and function as well as how they contribute to drug resistance and accelerated cancer evolution. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals HUMANIZED MICE: CREATION, MODELS AND USE IN EXPERIMENTAL ONCOLOGY (REVIEW)

Biomeditsina ◽  
2019 ◽  
pp. 67-81
Author(s):  
O. I. Kit ◽  
A. Yu. Maksimov ◽  
T. P. Protasova ◽  
A. S. Goncharova ◽  
D. S. Kutilin ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Human Cancer ◽  
Transgenic Animals ◽  
Humanized Mice ◽  
Humanized Mouse ◽  
Antitumour Agents ◽  
Human Genes ◽  
Oncology Review ◽  
Wide Range ◽  
Humanized Mouse Models

Research laboratories in various countries are constantly endeavouring to improve the existing and to create new biological objects to simulate various human diseases. Immunodefi cient mice with transplanted human functional cells and tissues, as well as transgenic animals with the relevant human genes integrated in their genome — i. e. humanized mice — are increasingly used as test systems in biomedical studies. Humanized mouse models are constantly being improved to fi nd application in studies investigating human biological reactions and identifying the pathogenetic mechanisms behind a wide range of diseases, or as preclinical tools for medicine testing. In particular, such animals play an increasingly important role both in studies of human-specifi c infectious agents, cancer biology research and in the development of new antitumour agents. In addition, humanized mice are increasingly used as translational models in many areas of clinical research, including transplantology, immunology and oncology. Ultimately, the use of humanized animals can lead to the introduction of a truly personalized medicine into clinical practice. In this review, we discuss modern advances in the creation and use of humanized mice, emphasizing their usefulness for the pathogenesis study, as well as the development of new methods for human cancer treatment.

scholarly journals Genome-Based Identification of Cancer Genes by Proviral Tagging in Mouse Retrovirus-Induced T-Cell Lymphomas

2003 ◽  
Vol 77 (3) ◽  
pp. 2056-2062 ◽  
Author(s):  
Rachel Kim ◽  
Alla Trubetskoy ◽  
Takeshi Suzuki ◽  
Nancy A. Jenkins ◽  
Neal G. Copeland ◽  
...  
Keyword(s):  
T Cell ◽  
Molecular Mechanisms ◽  
Mouse Genome ◽  
Human Cancer ◽  
Inverse Pcr ◽  
Ras Signaling ◽  
Cancer Genes ◽  
Altered Expression ◽  
New Genes ◽  
T Cell Lymphomas

ABSTRACT The identification of tumor-inducing genes is a driving force for elucidating the molecular mechanisms underlying cancer. Many retroviruses induce tumors by insertion of viral DNA adjacent to cellular oncogenes, resulting in altered expression and/or structure of the encoded proteins. The availability of the mouse genome sequence now allows analysis of retroviral common integration sites in murine tumors to be used as a genetic screen for identification of large numbers of candidate cancer genes. By positioning the sequences of inverse PCR-amplified, virus-host junction fragments within the mouse genome, 19 target genes were identified in T-cell lymphomas induced by the retrovirus SL3-3. The candidate cancer genes included transcription factors (Fos, Gfi1, Lef1, Myb, Myc, Runx3, and Sox3), all three D cyclins, Ras signaling pathway components (Rras2/TC21 and Rasgrp1), and Cmkbr7/CCR7. The most frequent target was Rras2. Insertions as far as 57 kb away from the transcribed portion were associated with substantially increased transcription of Rras2, and no coding sequence mutations, including those typically involved in Ras activation, were detected. These studies demonstrate the power of genome-based analysis of retroviral insertion sites for cancer gene discovery, identify several new genes worth examining for a role in human cancer, and implicate the pathways in which those genes act in lymphomagenesis. They also provide strong genetic evidence that overexpression of unmutated Rras2 contributes to tumorigenesis, thus suggesting that it may also do so if it is inappropriately expressed in human tumors.

scholarly journals The “false-positive” conundrum in the NTP 2-year rodent cancer study database

2018 ◽  
Vol 2 ◽  
pp. 239784731877283 ◽  
Author(s):  
Carr J. Smith ◽  
Thomas A. Perfetti
Keyword(s):  
Mutation Rate ◽  
Ames Test ◽  
Cellular Proliferation ◽  
Tumor Site ◽  
Routes Of Administration ◽  
Replication Errors ◽  
Background Mutation Rate ◽  
High Doses ◽  
Dna Replication Errors ◽  
Rats And Mice

In 1990, Ames and Gold described a conundrum of “too many carcinogens” among chemicals tested in rodent bioassays. Their proposed nongenotoxic carcinogenic mechanism was amplification of the background mutation rate via cytotoxicity induced by high doses of the test chemicals, thereby leading to increases in reparative cellular proliferation rates. Recently, we have statistically and mechanistically analyzed the entire 594-study (470 final reports) NTP 2-year rodent cancer database to better understand the conundrum posed by Ames and Gold. Our analysis provides several lines of evidence that support the contention of Ames and Gold. First, across different routes of administration, relatively phylogenetically similar rats and mice are nonetheless discordant for the development of tumors at similar organ sites. Tumor site concordance across sex within species is higher than tumor site concordance across species. Second, many chemicals negative in the Ames test nonetheless induce tumors in either rats or mice. Third, 11 out of 58 chemicals tested by the inhalation route induce lung tumors in mice and not rats, are negative in the Ames test, and exhibit hyperplasia. In 2017, Tomasetti et al. provided evidence for the clinical relevance in humans of the Ames and Gold mechanism regarding amplification of the background mutation rate by demonstrating that the majority of human tumors result from accumulated mutations due to DNA replication errors.

A census of amplified and overexpressed human cancer genes

2010 ◽  
Vol 10 (1) ◽  
pp. 59-64 ◽  
Author(s):  
Thomas Santarius ◽  
Janet Shipley ◽  
Daniel Brewer ◽  
Michael R. Stratton ◽  
Colin S. Cooper
Keyword(s):  
Human Cancer ◽  
Cancer Genes

Abstract 4322: The landscape of mitochondrial DNA mutations in human cancer

2014 ◽  
Author(s):  
Young Seok Ju ◽  
Ludmil Alexandrov ◽  
Moritz Gerstung ◽  
Inigo Martincorena ◽  
Mike Stratton ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Human Cancer ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations
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