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Prokofyeva D.,Hannover Medical School | Prokofyeva D.,Bashkir State University | Bogdanova N.,Hannover Medical School | Dubrowinskaja N.,Hannover Medical School | And 13 more authors.
Breast Cancer Research and Treatment | Year: 2013

Bloom's syndrome is a rare autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia, including breast cancer. Whether monoallelic BLM mutations predispose to breast cancer has been a long-standing question. A nonsense mutation, p.Q548X, has recently been associated with an increased risk for breast cancer in a Russian case-control study. In the present work, we have investigated the prevalence of this Slavic BLM founder mutation in a total of 3,188 breast cancer cases and 2,458 controls from Bashkortostan, Belarus, Ukraine, and Kazakhstan. The p.Q548X allele was most frequent in Russian patients (0.8 %) but was also prevalent in Byelorussian and Ukrainian patients (0.5 and 0.6 %, respectively), whereas it was absent in Altaic or other non-European subpopulations. In a combined analysis of our four case-control series, the p.Q548X mutation was significantly associated with breast cancer (Mantel-Haenszel OR 5.1, 95 % CI 1.2; 21.9, p = 0.03). A meta-analysis with the previous study from the St. Petersburg area corroborates the association (OR 5.7, 95 % CI 2.0; 15.9, p = 3.7 × 10-4). A meta-analysis for all published truncating mutations further supports the association of BLM with breast cancer, with an estimated two- to five-fold increase in risk (OR 3.3, 95 %CI 1.9; 5.6, p = 1.9 × 10-5). Altogether, these data indicate that BLM is not only a gene for Bloom's syndrome but also might represent a breast cancer susceptibility gene. © 2012 Springer Science+Business Media New York.

Korytina G.,Institute of Biochemistry and Genetics | Kochetova O.,Institute of Biochemistry and Genetics | Akhmadishina L.,Institute of Biochemistry and Genetics | Viktorova E.,University of Gottingen | Victorova T.,Institute of Biochemistry and Genetics
Balkan Medical Journal | Year: 2012

Objective: To determine the prevalence of the most common allelic variants of CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2E1, CYP2F1, CYP2J2 and CYP2S1 in a representative sample of the three ethnic groups (Russians, Tatars and Bashkirs) from Republic of Bashkortostan (Russia), and compare the results with existing data published for other populations. Material and Methods: CYPs genotypes were determined in 742 DNA samples of healthy unrelated individuals representative of three ethnic groups. The CYPs gene polymorphisms were examined using the PCR-RLFP method. Results: Analysis of the CYP1A1 (rs1048943, rs4646903), CYP1A2 (rs762551), CYP2E1 (rs2031920) allele, genotype and haplotype frequencies revealed significant differences among healthy residents of the Republic of Bashkortostan of different ethnicities. Distribution of allele and genotype frequencies of CYP1A2 (rs35694136), CYP1B1 (rs1056836), CYP2C9 (rs1799853, rs1057910), CYP2F1 (rs11399890), CYP2J2 (rs890293), CYP2S1 (rs34971233, rs338583) genes were similar in Russians, Tatars, and Bashkirs. Analysis of the CYPs genes allele frequency distribution patterns among the ethnic groups from the Republic of Bashkortostan in comparison with the different populations worldwide was conducted. Conclusion: The peculiarities of the allele frequency distribution of CYPs genes in the ethnic groups of the Republic of Bashkortostan should be taken into consideration in association and pharmacogenetic studies. The results of the present investigation will be of great help in elucidating the genetic background of drug response, susceptibility to cancer and complex diseases, as well as in determining the toxic potentials of environmental pollutants in our region. © Trakya University Faculty of Medicine.

Korytina G.F.,Institute of Biochemistry and Genetics | Akhmadishina L.Z.,Institute of Biochemistry and Genetics | Viktorova E.V.,University of Gottingen | Tselousova O.S.,Institute of Biochemistry and Genetics | And 3 more authors.
Journal of Human Genetics | Year: 2013

We investigated the association of matrix metalloproteinases, the disintegrin and metalloprotease 33 and the tissue and serum inhibitors of proteinase gene polymorphisms with severe chronic respiratory diseases in Tatar children. We analyzed the case-control data sample from a total of 592 Tatar individuals, consisting of 119 children with chronic bronchitis, 138 with recurrent pneumonia and 335 control children residing in Ufa (Russia). The percentage of heterozygous genotype for the MMP9 (2660A>G) was higher among healthy children (52.54% vs 36.13% in chronic bronchitis patients, P adj =0.0033, P cor =0.033, odds ratio (OR)=0.51; and 36.96% in recurrent pneumonia group, P adj =0.0034, P cor =0.034, OR=0.53). The MMP12 (-82A>G) locus was associated with chronic bronchitis in the additive model (P adj =0.0091, P cor =0.09, OR=0.45, β=-0.798). The relationship between the 6A6A genotype of MMP3 (-1171 5A>6A) (P adj =0.0013, P cor =0.013, OR=3.91) and the 6A-A haplotype of MMP3 (-1171 5A>6A) and MMP12 (-82A>G) and recurrent pneumonia were unraveled (P adj =0.001, P cor =0.01, OR=2.07). This haplotype was also associated with a higher risk of chronic bronchitis (P adj =0.0012, P cor =0.012, OR=2.15). The TIMP3 (-1296T>C) was associated with recurrent pneumonia in the dominant model (P adj =0.0031, P cor =0.031, OR=1.91). The MMP9, MMP3 and TIMP3 (tissue inhibitors of matrix metalloproteinases) polymorphisms and MMP3 and MMP12 haplotypes may play a substantial role in susceptibility to severe airway and lung injury in children with chronic bronchitis and recurrent pneumonia. © 2013 The Japan Society of Human Genetics All rights reserved.

Agency: Cordis | Branch: FP7 | Program: CP-FP-SICA | Phase: HEALTH.2011.2.4.3-4 | Award Amount: 4.32M | Year: 2012

MEDIGENE project will study genetic and environmental (G x E) determinants of the metabolic syndrome (MetS) in recent immigrants in Europe by a novel approach integrating ancestry of Mediterranean populations in epidemiology, locus refining and Genome Wide Association Studies (GWAS). West Mediterranean shores are place of pre-historical termini of population expansion from Southern Europe and North Africa. Archaeogenetic studies in Europe indicated that Y chromosome and mitochondrial DNA patterns or Ancestry Informative Markers (AIMs) revealed a close relationship between genetic and geographic distances able to locate an individual DNA within few hundred kilometers. The project will use this information in mapping the genetic basis of insulin resistance, cardiovascular and metabolic complications in immigrants (Albanians, Romanians, Turkish, Tunisians, Algerians and Morocco) in host countries France, Spain, Italy and Greece. Ancestry markers and studies on ancient DNA from Roman historical migration in Catalonia will help to give a better picture of the genetic landscape of Europe and North Africa. Genes for MetS will be studied in existing samples from host and home countries by GWAS, locus refining by next-generation sequencing and haplotype mapping. Informative filtered SNPs will be then used in epidemiology and novel DNA samples to reveal G x E interactions and specificities of the pathogenesis of MetS. Genetic findings will be replicated in home countries (Anatolia and North Africa) in the goal to develop markers ethnic specific and significant at a clinical scale. Major impact is expected from dissemination of our findings to prevent the occurrence of MetS and obesity in children and adolescents or in descendants of modern immigration, understanding variability clinical manifestations of MetS in the context of malnutrition and from the novel approach of GWAS strategies by ameliorating the association signal and bursting R&D activities of SMEs.

Sampurna Chatterjee,Max Planck Institute for Neurological Research | Heukamp L.C.,University of Cologne | Siobal M.,Max Planck Institute for Neurological Research | Schottle J.,Max Planck Institute for Neurological Research | And 16 more authors.
Journal of Clinical Investigation | Year: 2013

The molecular mechanisms that control the balance between antiangiogenic and proangiogenic factors and initiate the angiogenic switch in tumors remain poorly defined. By combining chemical genetics with multimodal imaging, we have identified an autocrine feed-forward loop in tumor cells in which tumor-derived VEGF stimulates VEGF production via VEGFR2-dependent activation of mTOR, substantially amplifying the initial proangiogenic signal. Disruption of this feed-forward loop by chemical perturbation or knockdown of VEGFR2 in tumor cells dramatically inhibited production of VEGF in vitro and in vivo. This disruption was sufficient to prevent tumor growth in vivo. In patients with lung cancer, we found that this VEGF:VEGFR2 feed-forward loop was active, as the level of VEGF/VEGFR2 binding in tumor cells was highly correlated to tumor angiogenesis. We further demonstrated that inhibition of tumor cell VEGFR2 induces feedback activation of the IRS/MAPK signaling cascade. Most strikingly, combined pharmacological inhibition of VEGFR2 (ZD6474) and MEK (PD0325901) in tumor cells resulted in dramatic tumor shrinkage, whereas monotherapy only modestly slowed tumor growth. Thus, a tumor cell-autonomous VEGF:VEGFR2 feed-forward loop provides signal amplification required for the establishment of fully angiogenic tumors in lung cancer. Interrupting this feed-forward loop switches tumor cells from an angiogenic to a proliferative phenotype that sensitizes tumor cells to MAPK inhibition.

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