| 11. |
- Niazi, Yasmeen, et al.
(författare)
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Genetic variation associated with chromosomal aberration frequency : A genome-wide association study
- 2018
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Ingår i: Environmental and Molecular Mutagenesis. - : Wiley. - 0893-6692 .- 1098-2280.
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomal aberrations (CAs) in human peripheral blood lymphocytes (PBL) measured with the conventional cytogenetic assay have been used for human biomonitoring of genotoxic exposure for decades. CA frequency in peripheral blood is a marker of cancer susceptibility. Previous studies have shown associations between genetic variants in metabolic pathway, DNA repair and major mitotic checkpoint genes and CAs. We conducted a genome-wide association study on 576 individuals from the Czech Republic and Slovakia followed by a replication in two different sample sets of 482 (replication 1) and 1288 (replication 2) samples. To have a broad look at the genetic susceptibility associated with CA frequency, the sample sets composed of individuals either differentially exposed to smoking, occupational/environmental hazards, or they were untreated cancer patients. Phenotypes were divided into chromosome- and chromatid-type aberrations (CSAs and CTAs, respectively) and total chromosomal aberrations (CAtot). The arbitrary cutoff point between individuals with high and low CA frequency was 2% for CAtot and 1% for CSA and CTA. The data were analyzed using age, sex, occupation/cancer and smoking history as covariates. Altogether 11 loci reached the P-value of 10−5 in the GWAS. Replication 1 supported the association of rs1383997 (8q13.3) and rs2824215 (21q21.1) in CAtot and rs983889 (5p15.1) in CTA analysis. These loci were found to be associated with genes involved in mitosis, response to environmental and chemical factors and genes involved in syndromes linked to chromosomal abnormalities. Identification of new genetic variants for the frequency of CAs offers prediction tools for cancer risk in future. 2018 Wiley Periodicals, Inc.
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| 12. |
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| 13. |
- Thomsen, Hauke, et al.
(författare)
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Genomewide association study on monoclonal gammopathy of unknown significance (MGUS)
- 2017
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441. ; 99:1, s. 70-79
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To identify germ line variants contributing to the development of monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant precursor for multiple myeloma (MM).METHODS: We conducted the first genomewide association study (GWAS) on MGUS on 243 German cases with a replication on 294 Czech cases. Identified loci were further analyzed in 1508 German MM patients. New MM loci recently reported in a meta-analysis were also tested in the MGUS GWAS.RESULTS: In GWAS, we identified 10 loci contributing to development of MGUS at P-value threshold of 10-5 . The Czech cohort gave support for two associations (6q26, rs6933936; 7p21.3 rs10251201). In GWAS, rs974120 (8p23.2) reached genomewide significance (P=2.94×10-9 ), with a nominal significance in MM. The locus of rs974120 shows marks of transcriptional activity in leukemia according to ENCODE data. rs10251201 (7p21.3), rs9318227 (13q22.1), and rs10405859 (19q13.32) were associated with markers related to leukemogenesis and immune and inflammatory responses. Two newly identified candidate loci for MM, rs1948915 (8q24.21) and rs8058578 (16p11.2), were nominally associated with MGUS.CONCLUSIONS: These data allow a cautious first proposal for a germ line architecture of MGUS with links to leukemia and autoimmune conditions, the latter agreeing with a family study showing clustering of MGUS with autoimmune diseases.
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| 14. |
- Vodicka, Pavel, et al.
(författare)
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Genetic variation of acquired structural chromosomal aberrations
- 2018
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Ingår i: Mutation Research - Genetic Toxicology and Environmental Mutagenesis. - : Elsevier BV. - 1383-5718. ; 836, s. 13-21
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Tidskriftsartikel (refereegranskat)abstract
- Human malignancies are often hallmarked with genomic instability, which itself is also considered a causative event in malignant transformation. Genomic instability may manifest itself as genetic changes in the nucleotide sequence of DNA, or as structural or numerical changes of chromosomes. Unrepaired or insufficiently repaired DNA double-strand breaks, as well as telomere shortening, are important contributors in the formation of structural chromosomal aberrations (CAs). In the present review, we discuss potential mechanisms behind the formation of CAs and their relation to cancer. Based on our own studies, we also illustrate how inherited genetic variation may modify the frequency and types of CAs occurring in humans. Recently, we published a series of studies on variations in genes relevant to maintaining genomic integrity, such as those encoding xenobiotic-metabolising enzymes, DNA repair, the tumour suppressor TP53, the spindle assembly checkpoint, and cyclin D1 (CCND1). While individually genetic variation in these genes exerted small modulating effects, in interactions they were associated with CA frequencies in peripheral blood lymphocytes of healthy volunteers. Moreover, we observed opposite associations between the CCND1 splice site polymorphism rs9344 G870A and the frequency of CAs compared to their association with translocation t(11,14). We discuss the functional consequences of the CCND1 gene in interplay with DNA damage response and DNA repair during malignant transformation. Our review summarizes existing evidence that gene variations in relevant cellular pathways modulate the frequency of CAs, predominantly in a complex interaction. More functional/mechanistic studies elucidating these observations are required. Several questions emerge, such as the role of CAs in malignancies with respect to a particular phenotype and heterogeneity, the formation of CAs during the process of malignant transformation, and the formation of CAs in individual types of lymphocytes in relation to the immune response.
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| 15. |
- Vodicka, Pavel, et al.
(författare)
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Interactions of DNA repair gene variants modulate chromosomal aberrations in healthy subjects.
- 2015
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 36:11, s. 1299-1306
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Tidskriftsartikel (refereegranskat)abstract
- Human cancers are often associated with numerical and structural chromosomal instability. Structural chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBL) arise as consequences of direct DNA damage or due to replication on a damaged DNA template. In both cases, DNA repair is critical and inter-individual differences in its capacity are probably due to corresponding genetic variations. We investigated functional variants in DNA repair genes (base and nucleotide excision repair, double-strand break repair) in relation to CAs, chromatid-type aberrations (CTAs) and chromosome-type aberrations (CSAs) in healthy individuals. Chromosomal damage was determined by conventional cytogenetic analysis. The genotyping was performed by both restriction fragment length polymorphism and TaqMan allelic discrimination assays. Multivariate logistic regression was applied for testing individual factors on CAs, CTAs and CSAs. Pair-wise genotype interactions of 11 genes were constructed for all possible pairs of single-nucleotide polymorphisms. Analysed individually, we observed significantly lower CTA frequencies in association with XPD Lys751Gln homozygous variant genotype [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.48-0.85, P = 0.004; n = 1777]. A significant association of heterozygous variant genotype in RAD54L with increased CSA frequency (OR 1.96, 95% CI 1.01-4.02, P = 0.03) was determined in 282 subjects with available genotype. By addressing gene-gene interactions, we discovered 14 interactions significantly modulating CAs, 9 CTAs and 12 CSAs frequencies. Highly significant interactions included always pairs from two different pathways. Although individual variants in genes encoding DNA repair proteins modulate CAs only modestly, several gene-gene interactions in DNA repair genes evinced either enhanced or decreased CA frequencies suggesting that CAs accumulation requires complex interplay between different DNA repair pathways.
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| 16. |
- Vymetalkova, Veronika, et al.
(författare)
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Epigenome-wide analysis of DNA methylation reveals a rectal cancer-specific epigenomic signature
- 2016
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Ingår i: Epigenomics. - London, United Kingdom : Future Medicine Ltd.. - 1750-1911 .- 1750-192X. ; 8:9, s. 1193-1207
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The aim of the present study is to address a genome-wide search for novel methylation biomarkers in the rectal cancer (RC), as only scarce information on methylation profile is available.Materials and methods: We analyzed methylation status in 25 pairs of RC and adjacent healthy mucosa using the Illumina Human Methylation 450 BeadChip.Results: We found significantly aberrant methylation in 33 genes. After validation of our results by pyrosequencing, we found a good agreement with our findings. The BPIL3 and HBBP1 genes resulted hypomethylated in RC, whereas TIFPI2, ADHFE1, FLI1 and TLX1 were hypermethylated. An external validation by TCGA datasets confirmed the results.Conclusion: Our study, with external validation, has demonstrated the feasibility of using specific methylated DNA signatures for developing biomarkers in RC.
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