Copy number variation of MDM2 and p53 genes in extracellular DNA as potential marker for lung adenocarcinoma diagnostics.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23094-e23094
Author(s):  
Denis S. Kutilin ◽  
Yaroslav S. Enin ◽  
Dmitriy I. Vodolazhsky ◽  
Vyacheslav A. Sustretov ◽  
Tamara G. Ayrapetova ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Gene Copy Number ◽  
P53 Gene ◽  
Extracellular Dna ◽  
Gene Copy ◽  
Mdm2 Gene ◽  
Healthy Donors ◽  
Number Variation ◽  
P53 Genes

e23094 Background: Today, the problem of early diagnostics of lung cancer remains unsolved as every fourth patient diagnosed with the disease already has distant metastases. Studying gene copy number variation (CNV) in extracellular DNA in the blood plasma can become a basis for a new effective and low invasive method for predictive diagnostics and disease prognosis. The purpose of the study was to examine the copy number of the MDM2 and p53 genes in extracellular DNA of patients with metastatic and non-metastatic lung cancer and healthy donors. Methods: The blood samples of 30 patients with lung adenocarcinoma (collected before surgery) and 30 healthy donors (without cancer) were studied. Each sample was centrifuged to obtain blood plasma. DNA was isolated from plasma using a phenol-chloroform extraction method. Detection of relative copy number of the MDM2 and p53 genes (reference gene - GAPDH) was performed by RT-qPCR using CFX96 thermocycler (Bio-Rad, USA). The groups were compared by the Mann-Whitney U- test. Results: Reduction of the p53 gene copy number by 57% (p < 0.05), as well as increasing of the MDM2 gene copy number by 160% (p < 0.05), were found in the extracellular DNA of patients with lung adenocarcinoma compared with healthy donors. As a result, the ratio of copy number of pro-/anti-apoptotic genes p53:MDM2 in extracellular DNA of patients with lung adenocarcinoma (1:23 ratio) was different from that of healthy donors (1:4 ratio). The MDM2 gene copy number in extracellular DNA of patients with metastases exceeded the value in non-metastatic patients two-fold (p < 0.05). The p53 gene copy number in extracellular DNA of patients with metastatic and non-metastatic cancer did not differ significantly. Conclusions: CNV of the p53 and MDM2 genes in extracellular DNA has a high potential for low invasive diagnostics and prognosis of lung adenocarcinoma.

Genetic variability of CYP2D6, CYP3A4 and CYP3A5 among the Egyptian population

2021 ◽  
Author(s):  
Thuraya M Mutawi ◽  
Mohamed M Zedan ◽  
Raida S Yahya ◽  
Mahmoud M Zakria ◽  
Mamdouh R El-Sawi ◽  
...  
Keyword(s):  
Genetic Variability ◽  
Copy Number Variation ◽  
Copy Number ◽  
Middle Eastern ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Allelic Variants ◽  
Gene Copy Number Variation ◽  
Number Variation ◽  
Study Participants

Aim: This study investigated major allelic variants of CYP2D6, CYP3A4 and CYP3A5 in Egyptians, an Arabic population for which there is little information regarding these important pharmacogenes. Patients & methods: CYP2D6*2, *4, *5, *10, *41 and gene copy number variation, as well as CYP3A4*22 and CYP3A5*3 were determined with commercially available TaqMan assays in 145 healthy study participants. Results: The CYP2D6 alleles identified suggest that the prevalence of poor metabolizers is low as none were found among the 145 subjects investigated. The frequency for CYP3A5 nonexpressers was 74.5% and the CYP3A4*22 allele frequency was low at 2.0%. Conclusion: These preliminary findings indicate that pharmacogene variation in Egyptians is different from those of other Middle Eastern/Arabic populations and warrants further investigation.

Gene copy number variation in schizophrenia

2007 ◽  
Vol 96 (1-3) ◽  
pp. 93-99 ◽  
Author(s):  
S SUTRALA ◽  
D GOOSSENS ◽  
N WILLIAMS ◽  
L HEYRMAN ◽  
R ADOLFSSON ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Gene Copy Number Variation ◽  
Number Variation

scholarly journals Emergence of a Viral RNA Polymerase Variant during Gene Copy Number Amplification Promotes Rapid Evolution of Vaccinia Virus

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Kelsey R. Cone ◽  
Zev N. Kronenberg ◽  
Mark Yandell ◽  
Nels C. Elde
Keyword(s):  
Rna Polymerase ◽  
Vaccinia Virus ◽  
Copy Number ◽  
Point Mutations ◽  
Gene Copy Number ◽  
Viral Rna ◽  
Gene Copy ◽  
Trade Offs ◽  
Number Variation ◽  
Copy Number Amplification

ABSTRACT Viruses are under relentless selective pressure from host immune defenses. To study how poxviruses adapt to innate immune detection pathways, we performed serial vaccinia virus infections in primary human cells. Independent courses of experimental evolution with a recombinant strain lacking E3L revealed several high-frequency point mutations in conserved poxvirus genes, suggesting important roles for essential poxvirus proteins in innate immune subversion. Two distinct mutations were identified in the viral RNA polymerase gene A24R, which seem to act through different mechanisms to increase virus replication. Specifically, a Leu18Phe substitution encoded within A24R conferred fitness trade-offs, including increased activation of the antiviral factor protein kinase R (PKR). Intriguingly, this A24R variant underwent a drastic selective sweep during passaging, despite enhanced PKR activity. We showed that the sweep of this variant could be accelerated by the presence of copy number variation (CNV) at the K3L locus, which in multiple copies strongly reduced PKR activation. Therefore, adaptive cases of CNV can facilitate the accumulation of point mutations separate from the expanded locus. This study reveals how rapid bouts of gene copy number amplification during accrual of distant point mutations can potently facilitate poxvirus adaptation to host defenses. IMPORTANCE Viruses can evolve quickly to defeat host immune functions. For poxviruses, little is known about how multiple adaptive mutations emerge in populations at the same time. In this study, we uncovered a means of vaccinia virus adaptation involving the accumulation of distinct genetic variants within a single population. We identified adaptive point mutations in the viral RNA polymerase gene A24R and, surprisingly, found that one of these mutations activates the nucleic acid sensing factor PKR. We also found that gene copy number variation (CNV) can provide dual benefits to evolving virus populations, including evidence that CNV facilitates the accumulation of a point mutation distant from the expanded locus. Our data suggest that transient CNV can accelerate the fixation of mutations conferring modest benefits, or even fitness trade-offs, and highlight how structural variation might aid poxvirus adaptation through both direct and indirect actions.

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