MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms

High intra- and interindividual variations in the expression levels of the human O6-methylguanine-DNA methyltransferase (MGMT) gene have been observed. This DNA repair enzyme can be a cause of resistance of cancer cells to alkylating chemotherapy. It has been studied the association of single nucleo...

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Опубліковано в: :	Вiopolymers and Cell
Дата:	2013
Автори:	Iatsyshyna, A.P., Pidpala, O.V., Lukash, L.L.
Формат:	Стаття
Мова:	English
Опубліковано:	Інститут молекулярної біології і генетики НАН України 2013
Теми:	Reviews
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Цитувати:	MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms / A.P. Iatsyshyna, O.V. Pidpala, L.L. Lukash // Вiopolymers and Cell. — 2013. — Т. 29, №. 5. — С. 367-374. — Бібліогр.: 33 назв. — англ.

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spelling	Iatsyshyna, A.P. Pidpala, O.V. Lukash, L.L. 2019-06-13T12:36:30Z 2019-06-13T12:36:30Z 2013 MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms / A.P. Iatsyshyna, O.V. Pidpala, L.L. Lukash // Вiopolymers and Cell. — 2013. — Т. 29, №. 5. — С. 367-374. — Бібліогр.: 33 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00082B https://nasplib.isofts.kiev.ua/handle/123456789/153029 577.21:577.218 High intra- and interindividual variations in the expression levels of the human O6-methylguanine-DNA methyltransferase (MGMT) gene have been observed. This DNA repair enzyme can be a cause of resistance of cancer cells to alkylating chemotherapy. It has been studied the association of single nucleotide polymorphisms (SNPs) of MGMT with the risk for different types of cancer, progression-free survival in patients with cancer treated with alkylating chemotherapy, as well as an effect of SNPs on the MGMT gene expression and activity of the enzyme. SNPs have been suggested to be the factors which influence the levels of interindividual variability of the MGMT expression. Therefore, the aim of this paper was to review the experimental data on SNPs of the human MGMT gene, which are associated with cancer, as well as on location of MGMT-SNPs in regulatory and protein-coding regions of the gene in relation to its regulation. Lots of MGMT SNPs, which could affect the gene expression and result in interindividual MGMT variability or the enzyme resistance to pseudosubstrate inhibitors, have been re- vealed within the promoter and enhancer regions, the 5'- and 3'-UTRs and introns of the MGMT gene, as well as within the protein-coding region. Many of them may have regulatory effect. Відомо, що в рівнях експресії гена О6-метилгуанін-ДНК метилтрансфераза (MGMT) людини існують значні внутрішньо- та міжіндивідуальну варіації . Цей репаративний фермент може спричиняти стійкість ракових клітин до алкілувальної хіміотерапії. Вивчено асоціації однонуклеотидних поліморфізмі (ОНП) MGMT з ризиком багатьох типів раку, виживанням пацієнтів без прогресування захворювання після алкілувальної хіміотерапії, а також вплив ОНП на експресію гена MGMT та активність даного ферменту. Припускають, що ОНП є факторами, які чинять вплив на рівні міжіндивідуальної варіації експресії MGMT. В огляді розглянуто експериментальні дані щодо ОНП гена MGMT людини, асоційованих з раком, а також стосовно локалізації ОНП MGMT у регуляторних і білок-кодуючій ділянках гена, залучених до його регуляції. Значну кількість ОНП MGMT з потенційною здатністю впливати на експресію гена та спричиняти міжіндивідуальні варіації MGMT або на стійкість ферменту до псевдосубстратних інгібіторів виявлено у промоторній та енхансерній областях, 5'- і 3'-нетрансльованих ділянках та інтронах гена MGMT, а також у білок-кодуючій ділянці. Багато з них можуть слугувати регуляторними факторами. Известно, что существуют значительные внутри- и межиндивидуальные вариации уровней экспрессии гена О6-метилгуанин-ДНК метилтрансфераза (MGMT) человека. Этот рфермент репарации ДНК может быть причиной устойчивости раковых клеток к алкилирующей химиотерапии. Изучены ассоциации однонуклеотидных полиморфизмов (ОНП) MGMT с риском для различных типов рака, выживаемостью пациентов без прогрессирования заболевания после алкилирующей химиотерапии, а также влияние ОНП на экспрессию гена MGMT и активность этого фермента. Высказано предположение, что ОНП являются факторами, влияющими на межиндивидульные уровни вариабельности экспрессии MGMT. В обзоре рассмотрены экспериментальные данные относительно ОНП гена MGMT человека, ассоциированных с раком, а также по локализации ОНП MGMT в регуляторных и белок-кодирующих участках гена, причастных к регулированию. Большое количество ОНП MGMT с потенциальной способностью влиять на экспрессию гена и приводить к межиндивидуальной вариабельности MGMT или на стойкость фермента к псевдосубстратным ингибиторам выявлено в промоторной и энхансерной областях, 5'- и 3'-нетранслируемых участках и интронах гена MGMT, а также в белок-кодирующем участке. Многие из них могут служить регуляторными факторами. en Інститут молекулярної біології і генетики НАН України Вiopolymers and Cell Reviews MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms Експресія гена MGMT: розуміння її регуляції. 2. Однонуклеотидні поліморфізми Экспрессия гена MGMT: понимание ее регуляции. 2. Однонуклеотидные полиморфизмы Article published earlier
institution	Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection	DSpace DC
title	MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms
spellingShingle	MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms Iatsyshyna, A.P. Pidpala, O.V. Lukash, L.L. Reviews
title_short	MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms
title_full	MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms
title_fullStr	MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms
title_full_unstemmed	MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms
title_sort	mgmt expression: insights into its regulation. 2. single nucleotide polymorphisms
author	Iatsyshyna, A.P. Pidpala, O.V. Lukash, L.L.
author_facet	Iatsyshyna, A.P. Pidpala, O.V. Lukash, L.L.
topic	Reviews
topic_facet	Reviews
publishDate	2013
language	English
container_title	Вiopolymers and Cell
publisher	Інститут молекулярної біології і генетики НАН України
format	Article
title_alt	Експресія гена MGMT: розуміння її регуляції. 2. Однонуклеотидні поліморфізми Экспрессия гена MGMT: понимание ее регуляции. 2. Однонуклеотидные полиморфизмы
description	High intra- and interindividual variations in the expression levels of the human O6-methylguanine-DNA methyltransferase (MGMT) gene have been observed. This DNA repair enzyme can be a cause of resistance of cancer cells to alkylating chemotherapy. It has been studied the association of single nucleotide polymorphisms (SNPs) of MGMT with the risk for different types of cancer, progression-free survival in patients with cancer treated with alkylating chemotherapy, as well as an effect of SNPs on the MGMT gene expression and activity of the enzyme. SNPs have been suggested to be the factors which influence the levels of interindividual variability of the MGMT expression. Therefore, the aim of this paper was to review the experimental data on SNPs of the human MGMT gene, which are associated with cancer, as well as on location of MGMT-SNPs in regulatory and protein-coding regions of the gene in relation to its regulation. Lots of MGMT SNPs, which could affect the gene expression and result in interindividual MGMT variability or the enzyme resistance to pseudosubstrate inhibitors, have been re- vealed within the promoter and enhancer regions, the 5'- and 3'-UTRs and introns of the MGMT gene, as well as within the protein-coding region. Many of them may have regulatory effect. Відомо, що в рівнях експресії гена О6-метилгуанін-ДНК метилтрансфераза (MGMT) людини існують значні внутрішньо- та міжіндивідуальну варіації . Цей репаративний фермент може спричиняти стійкість ракових клітин до алкілувальної хіміотерапії. Вивчено асоціації однонуклеотидних поліморфізмі (ОНП) MGMT з ризиком багатьох типів раку, виживанням пацієнтів без прогресування захворювання після алкілувальної хіміотерапії, а також вплив ОНП на експресію гена MGMT та активність даного ферменту. Припускають, що ОНП є факторами, які чинять вплив на рівні міжіндивідуальної варіації експресії MGMT. В огляді розглянуто експериментальні дані щодо ОНП гена MGMT людини, асоційованих з раком, а також стосовно локалізації ОНП MGMT у регуляторних і білок-кодуючій ділянках гена, залучених до його регуляції. Значну кількість ОНП MGMT з потенційною здатністю впливати на експресію гена та спричиняти міжіндивідуальні варіації MGMT або на стійкість ферменту до псевдосубстратних інгібіторів виявлено у промоторній та енхансерній областях, 5'- і 3'-нетрансльованих ділянках та інтронах гена MGMT, а також у білок-кодуючій ділянці. Багато з них можуть слугувати регуляторними факторами. Известно, что существуют значительные внутри- и межиндивидуальные вариации уровней экспрессии гена О6-метилгуанин-ДНК метилтрансфераза (MGMT) человека. Этот рфермент репарации ДНК может быть причиной устойчивости раковых клеток к алкилирующей химиотерапии. Изучены ассоциации однонуклеотидных полиморфизмов (ОНП) MGMT с риском для различных типов рака, выживаемостью пациентов без прогрессирования заболевания после алкилирующей химиотерапии, а также влияние ОНП на экспрессию гена MGMT и активность этого фермента. Высказано предположение, что ОНП являются факторами, влияющими на межиндивидульные уровни вариабельности экспрессии MGMT. В обзоре рассмотрены экспериментальные данные относительно ОНП гена MGMT человека, ассоциированных с раком, а также по локализации ОНП MGMT в регуляторных и белок-кодирующих участках гена, причастных к регулированию. Большое количество ОНП MGMT с потенциальной способностью влиять на экспрессию гена и приводить к межиндивидуальной вариабельности MGMT или на стойкость фермента к псевдосубстратным ингибиторам выявлено в промоторной и энхансерной областях, 5'- и 3'-нетранслируемых участках и интронах гена MGMT, а также в белок-кодирующем участке. Многие из них могут служить регуляторными факторами.
issn	0233-7657
url	https://nasplib.isofts.kiev.ua/handle/123456789/153029
citation_txt	MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms / A.P. Iatsyshyna, O.V. Pidpala, L.L. Lukash // Вiopolymers and Cell. — 2013. — Т. 29, №. 5. — С. 367-374. — Бібліогр.: 33 назв. — англ.
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fulltext	UDC 577.21:577.218 MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms A. P. Iatsyshyna, O. V. Pidpala, L. L. Lukash Institute of Molecular Biology and Genetics, NAS of Ukraine 150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680 a.p.iatsyshyna@imbg.org.ua High intra- and interindividual variations in the expression levels of the human O6-methylguanine-DNA me- thyltransferase (MGMT) gene have been observed. This DNA repair enzyme can be a cause of resistance of cancer cells to alkylating chemotherapy. It has been studied the association of single nucleotide polymorphisms (SNPs) of MGMT with the risk for different types of cancer, progression-free survival in patients with cancer treated with alkylating chemotherapy, as well as an effect of SNPs on the MGMT gene expression and activity of the enzyme. SNPs have been suggested to be the factors which influence the levels of interindividual variability of the MGMT expression. Therefore, the aim of this paper was to review the experimental data on SNPs of the human MGMT ge- ne, which are associated with cancer, as well as on location of MGMT-SNPs in regulatory and protein-coding re- gions of the gene in relation to its regulation. Lots of MGMT SNPs, which could affect the gene expression and result in interindividual MGMT variability or the enzyme resistance to pseudosubstrate inhibitors, have been re- vealed within the promoter and enhancer regions, the 5'- and 3'-UTRs and introns of the MGMT gene, as well as within the protein-coding region. Many of them may have regulatory effect. Keywords: O 6 -methylguanine-DNA methyltransferase (MGMT), gene regulation, single nucleotide polymor- phism (SNP), transcription factor binding site. Introduction. The expression of the O6-methylguani- ne-DNA methyltransferase (MGMT), the DNA repair enzyme responsible for removing alkylation adducts from the O6-guanine in DNA, and its activity determine cell response to alkylating agents, including anticancer chemotherapy, preventing mutations and cell death. This enzyme can provide resistance of cancer cells to such the- rapy. The high intra- and interindividual variations in the MGMT expression levels have been observed, in- dicating to a complicated regulation of this gene [1, 2]. It has been suggested that single nucleotide poly- morphisms (SNPs) are the factors which influence the levels of interindividual variability of the MGMT ex- pression [3, 4]. The association of some MGMT poly- morphisms with the risk for different types of cancer, as well as the effects of polymorphic variations on the gene expression and activity of this enzyme are discus- sed in [3]. Many known SNPs of the human MGMT gene, which could affect the expression and result in interindividual MGMT variability or the resistance of the enzyme to pseudosubstrate inhibitors, have been re- vealed within the promoter and enhancer regions, the 5'- and 3'-UTRs and introns of the MGMT gene, as well as within the protein-coding region [3, 4]. It has been shown that at least two intragenic SNPs have the influ- ence upon an interindividual variation of the MGMT activity in peripheral blood mononuclear cells [5], as well as in normal human lung tissue [6]. Currently, disease- and trait-associated SNPs are ra- pidly being identified in the genome wide association studies and using related strategies [7]. The majority (~93 %) of these variants lie within non-coding se- quences, which are concentrated in regulatory DNA marked by deoxyribonuclease I (DNaseI) hypersensi- tive sites (DHSs) [8]. Thus, SNPs in functionally impor- tant non-coding DNA regions could make a significant 367 ISSN 0233–7657. Biopolymers and Cell. 2013. Vol. 29. N 5. P. 367–374 doi: 10.7124/bc.00082B � Institute of Molecular Biology and Genetics, NAS of Ukraine, 2013 contribution to the phenotypic variation and disease sus- ceptibility among individuals [9]. Evaluation of extent and number of SNPs detected within the human MGMT gene can be done by looking at the track of all SNPs in the protein-coding and non-coding regions including promoter from the UCSC genome browser (the Univer- sity of California Santa Cruz, Figure in Supplement). Since disease-associated SNPs systematically perturb the transcription factor (TF) recognition sequences and frequently alter allelic chromatin states, it is suggested the involvement of some SNPs in transcriptional regula- tory mechanisms, including modulation of promoter and enhancer elements and enrichment within the expres- sion quantitative trait loci [8]. In particular, SNPs in the regulatory non-coding regions can influence the DNA helical conformations, protein binding, methylation status of CpG dinucleotides, transcript splicing, etc. The aim of this paper is to review the experimental data on SNPs of the human MGMT gene, which are as- sociated with cancer, as well as on location of MGMT- SNPs in regulatory and protein-coding regions of the gene in relation to its regulation. This article is the se- cond part of a thematic series on the regulation of MGMT expression. SNPs in regulatory regions of the human MGMT gene. There are several known SNPs in the promoter, enhancer region, and introns of the human MGMT gene. They include G135T, G290A, C485A, C575A, G666A, C777A, G795C, A1034G and C1099T (numbered ac- cording to the X61657) [5, 10–12]. The X61657 is a ge- nomic clone 1157 base pairs in length which contains the sequence of the 5'-upstream region of the human MGMT gene with the promoter activity and the first un- translated exon, taken from the NIH genetic sequence database GenBank [13, 14]. We have aligned X61657 to chromosome 10 by using Nucleotide Blast program (http://blast.ncbi.nlm.nih.gov/Blast.cgi) and BLAT align- ment tool [15] (Fig. 1). 368 IATSYSHYNA A. P., PIDPALA O. V., LUKASH L. L. Tracks 1 2 3 4 5 6 7 500 bases hg 19 MGMT TSS 1 8 121 40 X61657 CpG island C-rich repeat Pol2 ELF (SC-631) Oct-2 TAF1 HEY1 c-Myc Pol2(phosphoS2) Pol2-4H8 c-Myc TAF1 E2F6_(H-50) Nrf1 HEY1 ELF1_ (SC-631) Pol2 Pol2-4H8 Egr-1 POU2F2 Fig. 1. Single nucleotide polymorphisms (SNPs) from ENCODE [18] within promoter region of the human MGMT gene. The open chromatin re- gion of MGMT promoter, marked by DHS and overlapped with TF ChIP-seq binding sites, is separated by straight lines: 1 – the human MGMT pro- moter X61657 from BLAT search; 2 – RefSeq gene and TSS location; 3 – DNaseI hypersensitive regions, marked as gray and dark boxes, darkness of which is proportional to the maximum signal strength observed in any cell line (the number to the left of the box shows how many cell lines are hypersensitive in the region); 4 – the track of TF ChIP-seq, which shows regions where TFs bind to DNA as assayed in different cell lines (the darkness of the box is proportional to the maximum signal strength observed in any cell line); 5 – CpG island; 6 – repeating elements (the open chromatin region contains C-rich repeat (Low complexity Family and Class), 156 bps in length at position chr10:131265319-131265474 on plus strand of DNA); 7 – single nucleotide polymorphisms track from dbSNP build 137 which have a minor allele frequency of at least 1 %, mapping only once to reference assembly The changes within the promoter and enhancer re- gions can affect the gene expression potentially, but it is difficult to check this, because many other factors can influence the MGMT expression. In particular, it is sug- gested that the C575A variant revealed in melanoma patients could influence the gene transcription [10], as it is located closely to the binding site (BS) with the eukaryotic heat shock factor [13]. The C1099T poly- morphism located within the enhancer region in the exon 1 [16] has been shown to increase the MGMT pro- moter-enhancer activity in luciferase assay [11]. Since recent numerous studies have identified ma- ny disease- and trait-related genetic variants [7], we ana- lysed the human MGMT gene non-coding and coding regions for SNP enrichment. The Fig. 1 presents a track that contains the information about SNPs located with- in an open chromatin area marked by DHS and over- lapped with TF ChIP-seq BSs [17, 18]. They include rs1625649; rs35322871; rs113813075; rs79442343; rs34180180; rs189357135; rs112837630; rs34138162; rs1623007; rs2782888; rs181536588; rs16906252; rs113327489; rs186050433; rs16906255; rs149452540 (Table 1). The location and data on SNPs were taken from the UCSC Genome Browser, the SNP database (dbSNP, build 137) at NCBI [17] and the SNPedia re- source, which is focused on the medical, phenotypic and genealogical associations of SNPs [19]. Some of the revealed SNPs are associated with can- cer. In particular, the TT genotype of rs1625649 loca- ted 523 bases upstream the transcription start site (TSS) of MGMT was found to correlate with a worse progres- sion-free survival in patients with metastatic colorectal cancer treated with oxaliplatin-based chemotherapy than the combined GG + GT genotypes [20]. The co- ding-synonimous polymorphism R (CGC) � R (CGT) in NM_002412 (rs16906252, Table 1) was found to have 369 MGMT EXPRESSION: INSIGHTS INTO ITS REGULATION. 2. SINGLE NUCLEOTIDE POLYMORPHISMS SNP ID from dbSNP/137 Position Strand Observed Reference allele Allele frequencies UCSC’s predicted function relative to MGMT gene tracks rs1625649 chr10:131264931 – G/T T G: 61.53 %; T: 38.47 % upstream_gene_variant (523 bases) rs35322871 chr10:131264957 + –/G G Not indicated upstream_gene_variant (497 bases) rs113813075 chr10:131265021 + A/C C A: 2.78 %; C: 97.22 % upstream_gene_variant (433 bases) rs79442343 chr10:131265102 + A/G G A: 4.39 %; G: 95.61 % upstream_gene_variant (352 bases) rs34180180 chr10:131265112 + A/G G A: 3.42 %; G: 96.58 % upstream_gene_variant (342 bases) rs189357135 chr10:131265135 + A/G G A: 0.41 %; G: 99.59 % upstream_gene_variant (319 bases) rs112837630 chr10:131265201 + G/T G Not indicated upstream_gene_variant (253 bases) rs34138162 chr10:131265223 + A/C C A: 5.35 %; C: 94.65 % upstream_gene_variant (231 bases) rs1623007 chr10:131265287 – A/T T A: 3.11 %; T: 96.89 % upstream_gene_variant (167 bases) rs2782888 chr10:131265328 – A/C A C: 0.091 %; G: 96.98 %; T: 2.93 % upstream_gene_variant (126 bases) rs181536588 chr10:131265388 + A/T T A: 10.03 %; T: 89.97 % upstream_gene_variant (66 bases) rs16906252 chr10:131265545 – A/G G A: 3.42 %; G: 96.58 % MGMT (NM_002412): synonymous_variant R (CGC) � R (CGT) rs113327489 chr10:131265576 + C/G G Not indicated intron_variant rs186050433 chr10:131265642 + C/T C C: 99.13 %; T: 0.87 % intron_variant rs16906255 chr10:131265665 – A/C A A: 8.02 %; C: 91.98 % intron_variant rs149452540 chr10:131265680 + A/C C A: 0.96 %; C: 99.04 % intron_variant Table 1 SNPs from dbSNP build 137 within open chromatin area of the human MGMT gene a strong association with the promoter methylation (silencing) in colorectal cancer [21, 22]. Also, it has been shown, that polymorphism C485A in promoter was as- sociated with increased risk of lung cancer in a Korean population, despite this SNP did not have an effect on the promoter activity [12]. Many other SNPs have been also found in introns (Suppl. Fig.). It has been shown that the A allele of the rs7087131 variant of the MGMT gene (chr10:131474474, plus DNA strand; ref. allele G) was associated with a decreased risk of esophageal squamous cell carcinoma [23], while rs12268840 (chr10:131325299, in intron 1, plus DNA strand) – with increased risks of adenocarci- noma of the esophagus [24]. We discussed in our previous paper [25] that pro- moter of the human MGMT gene from GenBank (X61657) contained TSS, which is located within the CpG island (CGI), DHS and exon 1 of the gene (Fig. 1). The overlapping of CGI and DHS marks the open chro- matin region and the location of active cis-regulatory elements. The ENCODE studies of different cell lines have demonstrated by using ChIP-seq (chromatin immunoprecipitation with antibodies specific to the TF followed by sequencing of the precipitated DNA), that the MGMT promoter can be targeted by several TFs in open chromatin region including c-Myc, E2F6, Egr-1, ELF1, HEY1, Nrf1, Oct-2, Pol2, POU2F2, TAF1 (Fig. 1, Table 2). TFBSs form two clusters located close to each other. It has been identified a 59 bp enhancer wi- thin the second cluster, which produced increased trans- criptional activity in a reporter gene assay and was re- quired for efficient promoter function [16]. This enhan- cer sequence is located at the first exon/intron at position +144 to +202 with respect to the TSS of the MGMT promoter X61657 [16]. This sequence overlaps with BSs for c-Myc, Oct-2, Pol2, POU2F2, TAF1 revealed in different cell types (Fig. 1). Since SNPs can perturb TF recognition sites, we have analyzed the DNA sequences around polymorphic nucleotides ± 20 bases for any changes (Fig. 2) using Match, which utilizes a library of positional weight matrices from TRANSFAC® Public 6.0 (http://www. gene-regulation.com/pub/programs.html#match), as well TFSEARCH program (http://www.cbrc.jp/research/ db/TFSEARCH.html). It has been revealed using Match, that polymorphic A allele of rs34180180 caused disap- pearance of BS for C/EBP (CCAAT/enhancer binding factor), and polymorphic C allele of rs16906255 for- 370 IATSYSHYNA A. P., PIDPALA O. V., LUKASH L. L. A B Reference allele Polymorphic allele Fig. 2. Examples of effect of polymorphic allele upon change of recognition motif for TF. Bioinformatic analysis has been done by using Match (A) and TFSEARCH (B) programs. Notes: matrix identifier, position (strand), core match, matrix match, sequence (always the plus strand is shown), factor name; TFMATRIX entries with High-scoring med BS for Pax-4 (member of the paired box family of TFs). Polymorphic A allele of rs189357135 has been shown by using TFSEARCH to create two new BSs for c-Ets-1 and Elk-1 (TCF) TFs, C allele of rs 2782888 – for SP1, and T allele of rs186050433 – for E47 TF. Thus, this short prediction analysis has shown a possible imp- lication of SNPs in the change of recognition sequences for TFs within the human MGMT promoter. Also, SNPs can change the methylation pattern of CGI of promoter and gene body, in particular due to the forming new or destruction of existing CpG dinucleotides in DNA. For example, in an open chromatin region of the given gene there are three SNPs (rs79442343, rs113327489, rs186050433), a reference allele of which forms CpG dinucleotide (Table 1). The rs2782888 SNP forms such dinucleotide, increasing a total number of CpG dinuc- leotides within CGI, methylation of which can poten- tially be attractive to binding with methyl-CpG binding proteins which in turn recruit histone deacetylase comp- lexes and cause the chromatin condensation [26]. Also, we have classified SNPs revealed from the open chromatin area of the human MGMT promoter by using Regulome database [27] to identify a putative re- gulatory potential and a functional role of variants (Tab- le 3). According to this database, only three of the ana- lyzed SNPs (rs112837630, rs2782888, rs16906255) belong to the group of variants, which likely affect TF binding, since these SNPs are located within TF bin- ding motif and DNase hypersensitive site [27]. How- ever, the Fig. 1 shows higher amount of such SNPs, which are located within an open chromatin area and may affect TF binding. This difference is probably cau- sed by the fact that RegulomeDB contains data from the old built 132 of dbSNP. SNPs in the protein-coding region of the human MGMT gene. SNPs in the protein-coding region of the MGMT gene were also found out in populations of healthy donors and patients with different types of can- cers. For instance, SNP at codon L53L (silent coding ef- fect) in exon 3 was detected in melanoma patients and healthy Swedish individuals [10, 28] and those from the UK [5], L84F (missense) in exon 3 – in melanoma patients and healthy individuals in Sweden [10, 28], lung patients and healthy controls from Poland [11] and in Caucasian population [29], as well as from the UK [5], I143V (rs2308321, missense) in exon 5 – in Swedish [10, 28], Polish [11], English [5] and Caucasian [29] po- pulations. SNP at codon G160R (missense) in exon 5 was detected in young patients with adult type cancers and in the control group [30]. K178R (rs2308327, missense) in exon 5 was identified in melanoma pati- ents and healthy individuals in Sweden [10, 28], in lung cancer patients and healthy donors from Poland [11] and the UK [5]. A silent SNP A197A in exon 5 was found in melanoma patients and healthy Swedish individuals [10]. Frequent in the human population polymorphic va- riants L84F, I143V and K178R are shown to have the same DNA repair efficiency as the wild-type MGMT enzyme, but they are more resistant to the pseudosub- 371 MGMT EXPRESSION: INSIGHTS INTO ITS REGULATION. 2. SINGLE NUCLEOTIDE POLYMORPHISMS Factor Position Genomic Size Cluster Score (out of 1000) Pol2 chr10:131264940-131265389 450 1000 Pol2 (phos- phoS2) chr10:131265030-131265313 284 351 Pol2-4H8 chr10:131265045-131265320 276 487 Pol2 chr10:131265442-131265759 318 918 Pol2-4H8 chr10:131265444-131265734 291 395 ELF1_(SC -631) chr10:131265006-131265281 276 157 ELF1_(SC -631) chr10:131265483-131265729 247 367 Oct-2 chr10:131265419-131265686 268 294 HEY1 chr10:131265510-131265642 133 242 HEY1 chr10:131265128-131265249 122 243 POU2F2 chr10:131265419-131265686 268 293 c-Myc chr10:131265081-131265290 210 236 c-Myc chr10:131265434-131265643 210 334 TAF1 chr10:131265086-131265349 264 311 TAF1 chr10:131265429-131265771 343 259 Nrf1 chr10:131265139-131265388 250 291 E2F6_(H- 50) chr10:131265205-131265404 200 84 Egr-1 chr10:131265216-131265431 216 376 Table 2 Transcription Factor ChIP-seq from ENCODE [18]: binding sites within open chromatin area of the human MGMT promoter strate inhibitors, such as O6-benzylguanine and O6-(4- bromothenyl) guanine, or PaTrin-2 [3, 4]. In particular, it has been revealed that I143V and I143V/K178R va- riants have no effect upon the DNA repair activity com- pared with the wild-type MGMT [28]. Despite I143V is located closely to the C145 residue at the active site of MGMT, this variant has been shown to have no effect on the activity of the enzyme, but it was more resistant to inactivation by the PaTrin-2 [5]. A higher sensitivity of proteins to inactivation by PaTrin-2 has been also observed for variants I143-K178 and I143-R178 com- parable with the V143-K178 and V143-R178 alleles [5]. SNPs L84F and I143V showed a statistically signifi- cantly increased risk of lung cancer in Caucasian popu- lation, especially in smoking women with non-small cell lung cancer [29], and of adenocarcinoma of the eso- phagus [24]. In another study, distributions of L53L and L84F polymorphisms did not significantly differ bet- ween the lung cancer patients and healthy controls [12]. I143V and K178R have been recently shown to corre- late with an increased risk of temozolomide-induced myelosuppression [31]. It has been shown that K178R is associated with increased risks of adenocarcinoma of the esophagus [24], lung cancer risk [32], and with co- lorectal cancer risk [33]. The association of MGMT polymorphisms with a risk for lung, breast, colorectal and endometrial cancer is reviewed in [3]. Conclusions. Many SNPs have been identified wi- thin the human MGMT gene coding and non-coding regions, in particular within the promoter region, 5'- and 3'-UTRs and introns. Some SNPs, which are detected in the open chromatin area of promoter region and marked by DHS, overlap with experimentally revealed in different cell lines TF BSs. Consequently, they can perturb these recognition sites, change methylation pat- tern, due to forming new or destruction of existing CpG dinucleotides in DNA, and as a result, such SNPs may affect the gene expression. The association of MGMT SNPs with the risk for different types of cancer, pro- gression-free survival in patients with cancer treated with alkylating chemotherapy, as well as an effect of SNPs on the gene expression, activity of this enzyme and its resistance to pseudosubstrate inhibitors were dis- cussed. Thus, SNPs can be the factors which influence the levels of interindividual variability of the MGMT expression. Acknowledgements. The study was supported by grant for Young Scientists from the National Academy of Sciences of Ukraine (0111U008220). À. Ï. ßöèøèíà, Î. Â. Ï³äïàëà, Ë. Ë. Ëóêàø Åêñïðåñ³ÿ ãåíà MGMT: ðîçóì³ííÿ ¿¿ ðåãóëÿö³¿. 2. Îäíîíóêëåîòèäí³ ïîë³ìîðô³çìè Ðåçþìå Â³äîìî, ùî â ð³âíÿõ åêñïðåñ³¿ ãåíà Î 6 -ìåòèëãóàí³í-ÄÍÊ ìåòèë- òðàíñôåðàçà (MGMT) ëþäèíè ³ñíóþòü çíà÷í³ âíóòð³øíüî- òà ì³æ³íäèâ³äóàëüíó âàð³àö³¿ . Öåé ðåïàðàòèâíèé ôåðìåíò ìîæå ñïðè÷èíÿòè ñò³éê³ñòü ðàêîâèõ êë³òèí äî àëê³ëóâàëüíî¿ õ³ì³îòå- ðàï³¿. Âèâ÷åíî àñîö³àö³¿ îäíîíóêëåîòèäíèõ ïîë³ìîðô³çì³ (ÎÍÏ) MGMT ç ðèçèêîì áàãàòüîõ òèï³â ðàêó, âèæèâàííÿì ïàö³ºíò³â áåç ïðîãðåñóâàííÿ çàõâîðþâàííÿ ï³ñëÿ àëê³ëóâàëüíî¿ õ³ì³îòåðàï³¿, à òàêîæ âïëèâ ÎÍÏ íà åêñïðåñ³þ ãåíà MGMT òà àêòèâí³ñòü äàíî- ãî ôåðìåíòó. Ïðèïóñêàþòü, ùî ÎÍÏ º ôàêòîðàìè, ÿê³ ÷èíÿòü âïëèâ íà ð³âí³ ì³æ³íäèâ³äóàëüíî¿ âàð³àö³¿ åêñïðåñ³¿ MGMT. Â îã- ëÿä³ ðîçãëÿíóòî åêñïåðèìåíòàëüí³ äàí³ ùîäî ÎÍÏ ãåíà MGMT ëþäèíè, àñîö³éîâàíèõ ç ðàêîì, à òàêîæ ñòîñîâíî ëîêàë³çàö³¿ ÎÍÏ MGMT ó ðåãóëÿòîðíèõ ³ á³ëîê-êîäóþ÷³é ä³ëÿíêàõ ãåíà, çàëó- ÷åíèõ äî éîãî ðåãóëÿö³¿. Çíà÷íó ê³ëüê³ñòü ÎÍÏ MGMT ç ïîòåí- ö³éíîþ çäàòí³ñòþ âïëèâàòè íà åêñïðåñ³þ ãåíà òà ñïðè÷èíÿòè ì³æ³íäèâ³äóàëüí³ âàð³àö³¿ MGMT àáî íà ñò³éê³ñòü ôåðìåíòó äî 372 IATSYSHYNA A. P., PIDPALA O. V., LUKASH L. L. dbSNP ID Category Other resources rs1625649 4 UCSC \| ENSEMBL \| dbSNP rs35322871 4 UCSC \| ENSEMBL \| dbSNP rs113813075 4 UCSC \| ENSEMBL \| dbSNP rs79442343 4 UCSC \| ENSEMBL \| dbSNP rs34180180 4 UCSC \| ENSEMBL \| dbSNP rs112837630 2b UCSC \| ENSEMBL \| dbSNP rs34138162 3a* UCSC \| ENSEMBL \| dbSNP rs1623007 4 UCSC \| ENSEMBL \| dbSNP rs2782888 2b UCSC \| ENSEMBL \| dbSNP rs16906252 4 UCSC \| ENSEMBL \| dbSNP rs113327489 4 UCSC \| ENSEMBL \| dbSNP rs16906255 2b UCSC \| ENSEMBL \| dbSNP Category Description: * (4) – Minimal TF binding evidence + DNase peak; (2b) – Likely to affect TF binding + any motif + DNase footprint + DNase peak; * (3a) – Less likely to affect TF binding + any motif + DNase peak. Table 3 Summary of analysis of SNPs located within the human MGMT promoter by using Regulome DB [27] within open chromatin area of the human MGMT promoter ïñåâäîñóáñòðàòíèõ ³íã³á³òîð³â âèÿâëåíî ó ïðîìîòîðí³é òà åí- õàíñåðí³é îáëàñòÿõ, 5'- ³ 3'-íåòðàíñëüîâàíèõ ä³ëÿíêàõ òà ³íòðî- íàõ ãåíà MGMT, à òàêîæ ó á³ëîê-êîäóþ÷³é ä³ëÿíö³. Áàãàòî ç íèõ ìîæóòü ñëóãóâàòè ðåãóëÿòîðíèìè ôàêòîðàìè. Êëþ÷îâ³ ñëîâà: Î 6 -ìåòèëãóàí³í-ÄÍÊ ìåòèëòðàíñôåðàçà (MGMT), ðåãóëÿö³ÿ åêñïðåñ³¿ ãåíà, îäíîíóêëåîòèäí³ ïîë³ìîðô³çìè (ÎÍÏ), ñàéò çâ’ÿçóâàííÿ ç òðàíñêðèïö³éíèì ôàêòîðîì. À. Ï. ßöûøèíà, Î. Â. Ïèäïàëà, Ë. Ë. Ëóêàø Ýêñïðåññèÿ ãåíà MGMT: ïîíèìàíèå åå ðåãóëÿöèè. 2. Îäíîíóêëåîòèäíûå ïîëèìîðôèçìû Ðåçþìå Èçâåñòíî, ÷òî ñóùåñòâóþò çíà÷èòåëüíûå âíóòðè- è ìåæèíäè- âèäóàëüíûå âàðèàöèè óðîâíåé ýêñïðåññèè ãåíà Î 6 -ìåòèëãóàíèí- ÄÍÊ ìåòèëòðàíñôåðàçà (MGMT) ÷åëîâåêà. Ýòîò ôåðìåíò ðå- ïàðàöèè ÄÍÊ ìîæåò áûòü ïðè÷èíîé óñòîé÷èâîñòè ðàêîâûõ êëåòîê ê àëêèëèðóþùåé õèìèîòåðàïèè. Èçó÷åíû àññîöèàöèè îäíî- íóêëåîòèäíûõ ïîëèìîðôèçìîâ (ÎÍÏ) MGMT ñ ðèñêîì äëÿ ðàç- ëè÷íûõ òèïîâ ðàêà, âûæèâàåìîñòüþ ïàöèåíòîâ áåç ïðîãðåññè- ðîâàíèÿ çàáîëåâàíèÿ ïîñëå àëêèëèðóþùåé õèìèîòåðàïèè, à òàêæå âëèÿíèå ÎÍÏ íà ýêñïðåññèþ ãåíà MGMT è àêòèâíîñòü ýòîãî ôåð- ìåíòà. Âûñêàçàíî ïðåäïîëîæåíèå, ÷òî ÎÍÏ ÿâëÿþòñÿ ôàêòîðà- ìè, âëèÿþùèìè íà ìåæèíäèâèäóëüíûå óðîâíè âàðèàáåëüíîñòè ýêñïðåññèè MGMT. Â îáçîðå ðàññìîòðåíû ýêñïåðèìåíòàëüíûå äàííûå îòíîñèòåëüíî ÎÍÏ ãåíà MGMT ÷åëîâåêà, àññîöèèðîâàí- íûõ ñ ðàêîì, à òàêæå ïî ëîêàëèçàöèè ÎÍÏ MGMT â ðåãóëÿòîð- íûõ è áåëîê-êîäèðóþùèõ ó÷àñòêàõ ãåíà, ïðè÷àñòíûõ ê ðåãóëèðî- âàíèþ. Áîëüøîå êîëè÷åñòâî ÎÍÏ MGMT ñ ïîòåíöèàëüíîé ñïî- ñîáíîñòüþ âëèÿòü íà ýêñïðåññèþ ãåíà è ïðèâîäèòü ê ìåæèíäèâè- äóàëüíîé âàðèàáåëüíîñòè MGMT èëè íà ñòîéêîñòü ôåðìåíòà ê ïñåâäîñóáñòðàòíûì èíãèáèòîðàì âûÿâëåíî â ïðîìîòîðíîé è ýí- õàíñåðíîé îáëàñòÿõ, 5'- è 3'-íåòðàíñëèðóåìûõ ó÷àñòêàõ è èíòðî- íàõ ãåíà MGMT, à òàêæå â áåëîê-êîäèðóþùåì ó÷àñòêå. Ìíîãèå èç íèõ ìîãóò ñëóæèòü ðåãóëÿòîðíûìè ôàêòîðàìè. Êëþ÷åâûå ñëîâà: Î 6 -ìåòèëãóàíèí-ÄÍÊ ìåòèëòðàíñôåðàçà (MGMT), ðåãóëÿöèÿ åêñïðåññèè ãåíà, îäíîíóêëåîòèäíûé ïîëèìîð- ôèçì (ÎÍÏ), ñàéò ñâÿçûâàíèÿ ñ òðàíñêðèïöèîííûì ôàêòîðîì. REFERENCES 1. Margison G. P., Povey A. C., Kaina B., Santibanez Koref M. F. Variability and regulation of O 6 -alkylguanine-DNA alkyltrans- ferase // Carcinogenesis.–2003.–24, N 4.–P. 625–635. 2. Kaina B., Christmann M., Naumann S., Roos W. P. MGMT: key node in the battle against genotoxicity, carcinogenicity and apop- tosis induced by alkylating agents // DNA Repair (Amst).– 2007.–6, N 8.–P. 1079–1099. 3. Bugni J. M., Han J., Tsai M. S., Hunter D. J., Samson L. D. Ge- netic association and functional studies of major polymorphic variants of MGMT // DNA Repair (Amst).–2007.–6, N 8.– P. 1116–1126. 4. Pegg A. E., Fang Q., Loktionova N. A. Human variants of O 6 -al- kylguanine-DNA alkyltransferase // DNA Repair (Amst).–2007.– 6, N 8.–P. 1071–1078. 5. Margison G. P., Heighway J., Pearson S., McGown G., Thornc- roft M. R., Watson A. J., Harrison K. L., Lewis S. J., Rohde K., Barber P. V., O'Donnell P., Povey A. C., Santibanez-Koref M. F. Quantitative trait locus analysis reveals two intragenic sites that influence O 6 -alkylguanine-DNA alkyltransferase activity in peripheral blood mononuclear cells // Carcinogenesis.–2005.– 26, N 8.–P. 1473–1480. 6. Heighway J., Margison G. P., Santibanez-Koref M. F. The alle- les of the DNA repair gene O 6 -alkylguanine-DNA alkyltransfe- rase are expressed at different levels in normal human lung tis- sue // Carcinogenesis.–2003.–24, N 10.–P. 1691–1694. 7. Stranger B. E., Stahl E. A., Raj T. Progress and promise of geno- me-wide association studies for human complex trait genetics // Genetics.–2011.–187, N 2.–P. 367–383. 8. Maurano M. T., Humbert R., Rynes E., Thurman R. E., Haugen E., Wang H., Reynolds A.P., Sandstrom R., Qu H., Brody J., Sha- fer A., Neri F., Lee K., Kutyavin T., Stehling-Sun S., Johnson A. K., Canfield T. K., Giste E., Diegel M., Bates D., Hansen R. S., Neph S., Sabo P. J., Heimfeld S., Raubitschek A., Ziegler S., Cotsapas C., Sotoodehnia N., Glass I., Sunyaev S. R., Kaul R., Stamatoyannopoulos J. A. Systematic localization of common disease-associated variation in regulatory DNA // Science.– 2012.–337, N 6099.–P. 1190–1195. 9. Vernot B., Stergachis A. B., Maurano M. T., Vierstra J., Neph S., Thurman R. E., Stamatoyannopoulos J. A., Akey J. M. Personal and population genomics of human regulatory variation // Geno- me Res.–2012.–22, N 9.–P. 1689–1697. 10. Egyhazi S., Ma S., Smoczynski K., Hansson J., Platz A., Ring- borg U. Novel O 6 -methylguanine-DNA methyltransferase SNPs: a frequency comparison of patients with familial melanoma and healthy individuals in Sweden // Hum. Mutat.–2002.–20, N 5.– P. 408–409. 11. Krzesniak M., Butkiewicz D., Samojedny A., Chorazy M., Rusin M. Polymorphisms in TDG and MGMT genes – epidemiologi- cal and functional study in lung cancer patients from Poland // Ann. Hum. Genet.–2004.–68, Pt 4.–P. 300–312. 12. Chae M. H., Jang J. S., Kang H. G., Park J. H., Park J. M., Lee W. K., Kam S., Lee E. B., Son J. W., Park J. Y. O 6 -Alkylguanine- DNA alkyltransferase gene polymorphisms and the risk of pri- mary lung cancer // Mol. Carcinog.–2006.–45, N 4.–P. 239–249. 13. Harris L. C., Potter P. M., Tano K., Shiota S., Mitra S., Brent T. P. Characterization of the promoter region of the human O 6 - methylguanine-DNA methyltransferase gene // Nucleic Acids Res.–1991.–19, N 22.–P. 6163–6167. 14. Benson D. A., Karsch-Mizrachi I., Lipman D. J., Ostell J., Sayers E. W. GenBank // Nucleic Acids Res.–2011.–39, Database is- sue.–P. D32–D37. 15. Kent W. J. BLAT – the BLAST-like alignment tool // Genome Res.–2002.–12, N 4.–P. 656–664. 16. Harris L. C., Remack J. S., Brent T. P. Identification of a 59 bp enhancer located at the first exon/intron boundary of the human O 6 -methylguanine DNA methyltransferase gene // Nucleic Acids Res.–1994.–22, N 22.–P. 4614–4619. 17. Sherry S. T., Ward M. H., Kholodov M., Baker J., Phan L., Smigi- elski E. M., Sirotkin K. dbSNP: the NCBI database of genetic variation // Nucleic Acids Res.–2001.–29, N 1.–P. 308–311. 18. Meyer L. R., Zweig A. S., Hinrichs A. S., Karolchik D., Kuhn R. M., Wong M., Sloan C. A., Rosenbloom K. R., Roe G., Rhead B., Raney B. J., Pohl A., Malladi V. S., Li C. H., Lee B. T., Learned K., Kirkup V., Hsu F., Heitner S., Harte R. A., Haeussler M., Gu- ruvadoo L., Goldman M., Giardine B. M., Fujita P. A., Dreszer T. R., Diekhans M., Cline M. S., Clawson H., Barber G. P., Haus- sler D., Kent W. J. The UCSC Genome Browser database: ex- tensions and updates 2013 // Nucleic Acids Res.–2013.–41, Da- tabase issue.–P. D64–D69. 19. Cariaso M., Lennon G. SNPedia: a wiki supporting personal ge- nome annotation, interpretation and analysis // Nucleic Acids Res.–2012.–40, Database issue.–P. D1308–D1312. 373 MGMT EXPRESSION: INSIGHTS INTO ITS REGULATION. 2. SINGLE NUCLEOTIDE POLYMORPHISMS 20. Park J. H., Kim N. S., Park J. Y., Chae Y. S., Kim J. G., Sohn S. K., Moon J. H., Kang B. W., Ryoo H. M., Bae S. H., Choi G. S., Jun S. H. MGMT -535G > T polymorphism is associated with prog- nosis for patients with metastatic colorectal cancer treated with oxaliplatin-based chemotherapy // J. Cancer Res. Clin. Oncol.– 2010.–136, N 8.–P. 1135–1142. 21. Ogino S., Hazra A., Tranah G. J., Kirkner G. J., Kawasaki T., Nosho K., Ohnishi M., Suemoto Y., Meyerhardt J. A., Hunter D. J., Fuchs C. S. MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer // Carcinogenesis.–2007.–28, N 9.– P. 1985–1990. 22. Hawkins N. J., Lee J. H., Wong J. J., Kwok C. T., Ward R. L., Hit- chins M. P. MGMT methylation is associated primarily with the germline C > T SNP (rs16906252) in colorectal cancer and nor- mal colonic mucosa // Mod. Pathol.–2009.–22, N 12.–P. 1588– 1599. 23. Akbari M. R., Malekzadeh R., Shakeri R., Nasrollahzadeh D., Foumani M., Sun Y., Pourshams A., Sadjadi A., Jafari E., Sotou- deh M., Kamangar F., Boffetta P., Dawsey S. M., Ghadirian P., Narod S. A. Candidate gene association study of esophageal squamous cell carcinoma in a high-risk region in Iran // Cancer Res.–2009.–69, N 20.–P. 7994–8000. 24. Doecke J., Zhao Z. Z., Pandeya N., Sadeghi S., Stark M., Green A. C., Hayward N. K., Webb P. M., Whiteman D. C.; Australian Cancer Study. Collaborators (77). Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcino- ma // Int. J. Cancer.–2008.–123, N 1.–P. 174–180. 25. Iatsyshyna A. P. MGMT expression: insights into its regulation. Part 1. Epigenetic factors // Biopolym. Cell.–2013.–29, N 2.– P. 99–106. 26. Jones P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond // Nat. Rev. Genet.–2012.–13, N 7.– P. 484–492. 27. Boyle A. P., Hong E. L., Hariharan M., Cheng Y., Schaub M. A., Kasowski M., Karczewski K. J., Park J., Hitz B. C., Weng S., Cherry J. M., Snyder M. Annotation of functional variation in personal genomes using RegulomeDB // Genome Res.–2012.– 22, N 9.–P. 1790–1797. 28. Ma S., Egyhazi S., Ueno T., Lindholm C., Kreklau E. L., Stierner U., Ringborg U., Hansson J. O 6 -methylguanine-DNA-methyl- transferase expression and gene polymorphisms in relation to chemotherapeutic response in metastatic melanoma // Br. J. Can- cer.–2003.–89, N 8.–P. 1517–1523. 29. Wang L., Liu H., Zhang Z., Spitz M. R., Wei Q. Association of ge- netic variants of O 6 -methylguanine-DNA methyltransferase with risk of lung cancer in non-Hispanic Whites // Cancer Epidemiol. Biomarkers Prev.–2006.–15, N 12.–P. 2364–2369. 30. Imai Y., Oda H., Nakatsuru Y., Ishikawa T. A polymorphism at codon 160 of human O 6 -methylguanine-DNA methyltransferase gene in young patients with adult type cancers and functional assay // Carcinogenesis.–1995.–16, N 10.–P. 2441–2445. 31. Sylvester R. K., Steen P., Tate J. M., Mehta M., Petrich R. J., Berg A., Kolesar J. Temozolomide-induced severe myelosup- pression: analysis of clinically associated polymorphisms in two patients // Anticancer Drugs.–2011.–22, N 1.–P. 104–110. 32. Crosbie P. A., McGown G., Thorncroft M. R., O’Donnell P. N., Barber P. V., Lewis S. J., Harrison K. L., Agius R. M., Santiba- nez-Koref M. F., Margison G. P., Povey A. C. Association bet- ween lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O 6 -alkyl- guanine-DNA alkyltransferase // Int. J. Cancer.–2008.–122, N 4.–P. 791–795. 33. Hazra A., Chanock S., Giovannucci E., Cox D. G., Niu T., Fuchs C., Willett W. C., Hunter D. J. Large-scale evaluation of genetic variants in candidate genes for colorectal cancer risk in the Nur- ses’ Health Study and the Health Professionals’ Follow-up Stu- dy // Cancer Epidemiol. Biomarkers Prev.–2008.–17, N 2.– P. 311–319. Received 01.03.13 374 IATSYSHYNA A. P., PIDPALA O. V., LUKASH L. L.

MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms

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