Novel epigenetic markers of early epithelial tumor growth and prognosis

Novel epigenetic markers of early epithelial tumor growth and prognosis

The present work is aimed at clarifying genetic and epigenetic alterations that occur during carcinogenesis and designing perspective sets of newly identified biomarkers. The tumors of kidney, cervix, colon, ovary, and lung were analyzed in our work, using the chromosome 3 specific NotI microarrays...

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Datum:2013
Hauptverfasser: Gordiyuk, V.V., Kondratov, A.G., Gerashchenko, G.V., Kashuba, V.I.
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Veröffentlicht: Інститут молекулярної біології і генетики НАН України 2013
Schriftenreihe:Вiopolymers and Cell
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Zitieren:Novel epigenetic markers of early epithelial tumor growth and prognosis / V.V. Gordiyuk, A.G. Kondratov, G.V. Gerashchenko, V.I. Kashuba // Вiopolymers and Cell. — 2013. — Т. 29, №. 3. — С. 215-220. — Бібліогр.: 27 назв. — англ.

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spelling irk-123456789-1525752019-06-13T01:26:22Z Novel epigenetic markers of early epithelial tumor growth and prognosis Gordiyuk, V.V. Kondratov, A.G. Gerashchenko, G.V. Kashuba, V.I. Reviews The present work is aimed at clarifying genetic and epigenetic alterations that occur during carcinogenesis and designing perspective sets of newly identified biomarkers. The tumors of kidney, cervix, colon, ovary, and lung were analyzed in our work, using the chromosome 3 specific NotI microarrays (NMA). We have found loci/genes with essential changes in gene methylation of tumor samples. Changes in expression for these genes were confirmed. The Not-I microarray results have been used to develop epigenetic marker panels for the early detection of different tumor types (ovary and lung cancer), to discriminate the stages of tumor growth and to determine whether the tumor is metastasizing. Marker panel designing is of great perspective in clinical medicine. В огляді розглянуто генетичні та епігенетичних зміни, які відбуваються при утворенні пухлин, та пошук перспективних наборів нових біомаркерів. Представлено дані NotI-мікрочіпів для 3-ї хромосоми людини щодо змін у пухлинах нирок, шийки матки, товстого кишечника, яєчників і легень. Знайдено локуси/гени з істотними змінами метилювання у зразках пухлин, які супроводжуються зниженням експресії відповідних генів. Результати мікрочіпів використано для розробки панелей епігенетичних маркерів ранньої детекції різних типів пухлин (яєчників і легенів), а також для розрізнення ступенів прогресії пухлин і виявлення метастазів. Створення подібних панелей маркерів є перспективним для засто- сування в клінічній медицині. В обзоре рассмотрены генетические и эпигенетические изменения,сопутствующие образованию опухолей, и поиск перспективных наборов новых биомаркеров. Представлены данные NotI-микрочипов для 3-й хромосомы человека относительно изменений в опухолях почек, шейки матки, толстого кишечника, яичников и легких. Найдены локусы/гены с существенными изменениями метилирования в образцах опухолей, сопровождающимися снижением экспрессии соответствующих генов. Результати микрочипов использованы для разработки панелей эпигенетических маркеров ранней детекции разних типов опухолей (яичников и легких), а также для дифференцирования степени прогрессии опухолей и выявления метастазов. Создание подобных панелей маркеров является перспективным для применения в клинической медицине. 2013 Article Novel epigenetic markers of early epithelial tumor growth and prognosis / V.V. Gordiyuk, A.G. Kondratov, G.V. Gerashchenko, V.I. Kashuba // Вiopolymers and Cell. — 2013. — Т. 29, №. 3. — С. 215-220. — Бібліогр.: 27 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00081B http://dspace.nbuv.gov.ua/handle/123456789/152575 577.218; 616.006.6 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України
institution Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection DSpace DC
language English
topic Reviews
Reviews
spellingShingle Reviews
Reviews
Gordiyuk, V.V.
Kondratov, A.G.
Gerashchenko, G.V.
Kashuba, V.I.
Novel epigenetic markers of early epithelial tumor growth and prognosis
Вiopolymers and Cell
description The present work is aimed at clarifying genetic and epigenetic alterations that occur during carcinogenesis and designing perspective sets of newly identified biomarkers. The tumors of kidney, cervix, colon, ovary, and lung were analyzed in our work, using the chromosome 3 specific NotI microarrays (NMA). We have found loci/genes with essential changes in gene methylation of tumor samples. Changes in expression for these genes were confirmed. The Not-I microarray results have been used to develop epigenetic marker panels for the early detection of different tumor types (ovary and lung cancer), to discriminate the stages of tumor growth and to determine whether the tumor is metastasizing. Marker panel designing is of great perspective in clinical medicine.
format Article
author Gordiyuk, V.V.
Kondratov, A.G.
Gerashchenko, G.V.
Kashuba, V.I.
author_facet Gordiyuk, V.V.
Kondratov, A.G.
Gerashchenko, G.V.
Kashuba, V.I.
author_sort Gordiyuk, V.V.
title Novel epigenetic markers of early epithelial tumor growth and prognosis
title_short Novel epigenetic markers of early epithelial tumor growth and prognosis
title_full Novel epigenetic markers of early epithelial tumor growth and prognosis
title_fullStr Novel epigenetic markers of early epithelial tumor growth and prognosis
title_full_unstemmed Novel epigenetic markers of early epithelial tumor growth and prognosis
title_sort novel epigenetic markers of early epithelial tumor growth and prognosis
publisher Інститут молекулярної біології і генетики НАН України
publishDate 2013
topic_facet Reviews
url http://dspace.nbuv.gov.ua/handle/123456789/152575
citation_txt Novel epigenetic markers of early epithelial tumor growth and prognosis / V.V. Gordiyuk, A.G. Kondratov, G.V. Gerashchenko, V.I. Kashuba // Вiopolymers and Cell. — 2013. — Т. 29, №. 3. — С. 215-220. — Бібліогр.: 27 назв. — англ.
series Вiopolymers and Cell
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AT kashubavi novelepigeneticmarkersofearlyepithelialtumorgrowthandprognosis
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fulltext UDC 577.218; 616.006.6 Novel epigenetic markers of early epithelial tumor growth and prognosis V. V. Gordiyuk, A. G. Kondratov, G. V. Gerashchenko, V. I. Kashuba Institute of Molecular Biology and Genetics, NAS of Ukraine 150, Akademika Zabolotnogo Str., Kyiv, Ukraine, 03680 vasilij_gordiyuk@yhoo.com The present work is aimed at clarifying genetic and epigenetic alterations that occur during carcinogenesis and designing perspective sets of newly identified biomarkers. The tumors of kidney, cervix, colon, ovary, and lung were analyzed in our work, using the chromosome 3 specific NotI microarrays (NMA). We have found loci/genes with essential changes in gene methylation of tumor samples. Changes in expression for these genes were con- firmed. The Not-I microarray results have been used to develop epigenetic marker panels for the early detection of different tumor types (ovary and lung cancer), to discriminate the stages of tumor growth and to determine whether the tumor is metastasizing. Marker panel designing is of great perspective in clinical medicine. Keywords: epithelial tumor, epigenetic markers, NotI-microarrays, early cancer detection, prognosis of cancer, tumor-suppressor gene. Introduction. An important problem in oncology is the creation of sets of markers for early differential diagno- sis of tumors, determining cancer progress and respon- se to therapy. Markers, which are already in use, are ef- fective at the later stages of tumor development. There- fore, it is necessary to intensify the search for new mar- kers, both, genetic and epigenetic, which reflect the changes at the early stages of carcinogenesis. The present work is aimed at clarifying genetic and epigenetic alterations that occur during carcinogenesis and designing perspective sets of newly identified bio- markers. Microarray analysis of large-scale searches for epigenetic changes in cancers (comparison of tumor versus normal tissues). NotI-microarray technology. The search for tumor markers is a complicated, multi- step process. The first step, usually, is the identification of large-scale genetic and/or epigenetic changes of the genome. The new type of microarrays that was recently developed in our group opens new possibilities for ex- tensive studies of methylation patterns in normal and cancer tissues [1]. The main objective was to prepare NotI microarrays (NMA, i. e. glass microarrays with attached NotI DNA fragments) for comparing the nor- mal and malignant cell genomes. Since the NotI enzy- me cuts only unmethylated CpG pairs in the recogni- tion site, (5'-GCGGCCGC-3'), only a small fraction of the NotI digested fragments (0.1–0.5 %) becomes labe- led [2]. Thus, in contrast to all other methods, only di- gested DNA fragments were labeled. As a consequen- ce, the probes contained 10-fold less repeats, were less sensitive to incomplete digestion, and gave less back- ground. A simplified scheme of a NotI microarray analy- sis protocol is presented in Fig. 1. Results and confirmation of the NotI microarray analysis of epithelial tumors. It is known, that the short arm of human chromosome 3 is involved in the development of many epithelial cancers [3–7]. Epithe- lial tumors make up ~ 90 % of all malignant tumors. The tumors of kidney, cervix, colon, ovary, and lung were analyzed in our work, using the chromosome 3 specific NotI microarrays (NMA), which contained 180 NotI linking clones, associated with 188 genes [8]. For all studied cancers we found genes, specifically methyla- 215 ISSN 0233–7657. Biopolymers and Cell. 2013. Vol. 29. N 3. P. 215–220 doi: 10.7124/bc.00081B � Institute of Molecular Biology and Genetics, NAS of Ukraine, 2013 216 ted in malignant cells. Many genes were methylated in a very high percentage of cancer samples. These genes can be divided into two classes: cancer specific and com- mon for several types of cancer. The genes, MINT24, BHLB2, GATA-2, RARB1, RBSP3, VHL, LRRC3B [1], were involved in several cancers. Interestingly, many methylated genes were prevoius- ly unknown to be involved in the development of epi- thelial cancers. To prove the methylation status of ge- nes that were observed by NMA hybridization, the me- thyl specific PCR (MSP) and bisulfite sequencing were performed. Genes that changed methylation status have been further investigated by relative genes expression, using Q-PCR [9]. Below we present some examples of changes in epi- genetic profiles of certain genes in epithelial tumors. Pri- mary tumors of different types of non-small cell lung car- cinoma (NSCLC) were studied [10], namely, squamous cell carcinoma (SCC), and adenocarcinoma (ADC) (Fig. 2, A, Supplement) [11]. Results of the NMA hybridization have shown that 44 loci/genes were methylated and/or deleted with a frequency from 15 to 58 % (Fig. 2, B, Supplement) [11]. Methylation was observed at stage I of SCC tumors. In ADC any of the genes showed methylation patterns, characteristic for tumor progression stage. From the frequently methylated genes by NMA, two genes were chosen and their methylation was addi- tionally tested, using bisulfite sequencing – VHL (in one SCC tumor sample and one ADC –tumor sample) and ITGA9 (in four SCC tumor samples). In all tested cases the methylation pattern was confirmed [11]. Ten genes that showed high methylation and/or de- letion frequencies in NSCLC were tested for expres- sion; these genes were expressed at the decreased level in 30–90 % of ADC cases and 38–100 % of SCC cases (Fig. 3). In general, the mRNA level in SCC samples was more frequently down-regulated than in ADC (sta- tistically valid for ITGA9 (P = 0.02) and FOXP1 (P = = 0.05) genes). In SCC, down-regulation was observed in 70 % of samples already at stage I, and in ADC – only in 45 %. Seven genes (except LRRN1, FGD5 and ALDH1L1) showed increased frequencies and/or down regulated expression upon the metastasizing of ADC (P < 0.05 for RBSP3 (CTDSPL) and ITGA9 genes). The same tendencies were observed for other 5 genes in SCC (IQSEC1, FOXP1 (P < 0.05), LRRN1, FGD5 and BCL6 [11]). The NMA was used to analyze other types of can- cers, namely, tumors of the cervix. 17 NotI-linking clones were detected that showed changes in more than 35 % of all of investigated tumor samples. The 7 of them were associated with other human cancers: MINT24, BHLHB2, ITGA9, RPL15, RARbeta1, RBSP3, and VHL. Some of them are accepted tumor suppressor genes, for example, LRRC3B and WNT7A [12, 13]. The 27 genes/loci showed differential expression in colorectal cancers compared with normal tissues in mo- re than 30% of the tumor samples. [14]. The 6 genes/ loci of the 27 were specific for colorectal cancer. The role of this six genes/loci (CKLFSF6, PLCL2, LMCD1, NUDT16P, LOC131961 and LOC650370) in the initia- tion and progression of tumors remains unknown and further study is required. Several genes/loci that were identified in our study as altered genes include previous- ly described bona fide tumor suppressor genes: VHL, RBSP3, WNT7A, ITGA9, and FOXP1 [15]. GORDIYUK V. V., KONDRATOV A. G., GERASHCHENKO A. V., KASHUBA V. I. Fig. 1. A simplified scheme of the NotI mic- roarray analysis protocol: A – isolation of ge- nomic DNA; B – digestion with the methyl- specific rare-cutter enzyme NotI; C – ligation of fragments with the NotI-linker containing biotin; D – digestion with the 4-base pair re- cognizing restriction enzyme Sau3AI; E – con- jugation to microbeads, containing streptavi- din and washing; F – amplification of DNA se- quences that have been attached to microbeads. The standard procedures were performed then: microarray hybridization, cloning, and sequen- cing analysis NMA of ovarian cancers has revealed that 35 genes showed the highest percentage of alterations (methyla- tion and/or deletion). The 17 genes/loci showed chan- ges in more than 30 % of ovarian tumor samples, regard- less whether the tumors were malignant or benign [16]. The most essential changes in tumor samples were found for LRRC3B (80 %), RARB (73 %), GATA2, and NKIRAS1 (66 %) genes [17]. NMA results have shown that the majority of genes with high frequency of changes in epithelial cancers are located on 3p21 and 3p24 regions [18–21]. Several genes were selected and further analyzed. For example, methylation of the LRRC3B gene in colo- rectal cancer was investigated, and, based on the obtai- ned results, this gene was proposed as a methylsensi- tive gene for diagnostics [22]. Also, the expression of LRRC3B gene in breast, cervical, lung, RCC, ovarian, and colon cancers was tested, using Q-PCR. LRRC3B gene expression was unchanged in ccRCC at stages I and II, however, it was 26-fold decreased in tumors at stage III. Noteworthy, this gene did not show differen- ce in the expression pattern in ovarian cancers without metastases, while it was 46-fold decreased in a sample with lymph node metastases (T3N1M0) and 107-fold less in a sample with distant metastases (T4N1M1) [23]. Using NMA technology the set of frequently affec- ted genes/loci of chromosome 3 was revealed in renal cell carcinomas (RCC’s) [20]. Briefly, we have identifi- ed 15 genes, which had genetic (deletion, amplifica- tion) and/or epigenetic (DNA methylation/demethy- lation) alterations in more than 30 % of RCC samples. Among frequently affected genes were NKIRAS1/ RPL15, MINT24, LRRC3B, VHL, RBSP3, GORASP1, RARB, NBEAL2, GNAI, PPM1M, FOXP1 and ZIC4. Additionally, using NMA we have detected the genetic/ epigenetic changes for some cancer associated genes li- ke WNT7A, FOXP1 and ITGA9 in ccRCC’s [20]. We have performed the NMA data verification by routine methods for some of the identified genes. Thus, we showed hypermethylation of the LRRC3B promoter CpG-island in 43 % of clear cell RCC’s [12]. More- over, the restoration of LRRC3B expression led to a sig- nificant decrease of colony formation by KRC/Y cell line [23]. It was identified that the NKIRAS1 expression was down-regulated in 75 % of ccRCC samples (9 of 12) compared to surrounding normal tissue. This was ac- companied by copy number change of the NKIRAS1 gene, which was observed in 64 % (9 of 14) of ccRCC samples [17]. Hypermethylation and high deletion fre- quency of the WNT7A gene were detected in 66 % (29/ 44) and 85% (23/27) of analyzed ccRCC’s. In addition, the re-expression of WNT7A led to inhibition of the pro- liferation rate in RCC cell lines [13]. Therefore, ap- plication of NMA technology contributed to identifica- tion of the frequently hypermethylated genes in ccRCC. Subsequently we have used the newly detected LRRC3B gene in combination with well-known hyper- methylated genes such as APC and FHIT to create a methylation-based biomarker panel for diagnostics of RCC [24–26]. We have detected hypermethylation of LRRC3B, FHIT and APC genes in 33.3 %, 27.8 % and 33.8 % of plasma samples of the RCC patients. These data emphasize the perspective application of NMA te- 217 NOVEL EPIGENETIC MARKERS OF EARLY EPITHELIAL TUMOR GROWTH AND PROGNOSIS Lung squamous cell carcinoma Lung adenocarcinoma IQSEC1 CTDSPL ITGA9 FOXP1 LRRN1 GNAI2 VHL FGD5 ALDHIL1 BCL6 R el a ti ve m R N A le ve l – without metastases – with metastases Fig. 3. Relative expression levels of 10 genes in NSCLC (SCC and ADC) chnology for identification of new methylation-based biomarkers [27]. Selection of genes/biomarkers for detection and status of epithelial cancers. Thus, we have completed the first stage of the search for biomarkers. We found a number of epigenetic changes in certain genes in diffe- rent tumor types. The next step was to select genes for biomarker panels. One of the examples of such panels to distinguish benign and malignant tumors was the NotI- linking clones forming DNA-microarray chips. These panels were used to investigate lung and ovary cancers [11, 16]. If methylation and/or deletion were found in two or more genes of a biomarker panel, such sets would be then recognized as specific groups. In this way, the NMA results afforded an opportunity to select some of the genes with high levels of epigenetic changes for the next stage of marker detection. A cluster analysis per- mits the putative gene selection to discriminate diffe- rent stages of cancerogenesis. Based on our results, we can propose a set of 8 genes for detection of NSCLC in lung biopsies of all stages, including stage I (Table 1, A) [11]. To select the genes that can help to discriminate ADC without metastases from the three other groups, i. e., ADC with metastases, SCC without and with meta- stases, was quite easy, using [the] data, obtained by NotI microarray analysis. To distinguish ADC from SCC, the most promising set should include NKIRAS1/ RPL15, CGGBP1, VHL, LOC285375, EPHB1, BHL HE40, and ANKRD28 biomarkers (Table 1, B) [11]. For discrimination between ADC without and with metastases, it is possible to use LRRC3B, UBE2E2, WNT7A, and FGD5 set of biomarkers (Table 1, C) [11]. Using the obtained NotI microarrays data with com- paratively small number of samples, it was quite diffi- cult to discriminate between SCC cases without and with metastases (Table 1, D) [11]. The most suitable set con- sists of only three genes (GORASP1/TTC21A, LRRN1, and VHL) that showed increased frequencies of methy- lation and/or deletion upon progression of SCC, and one gene – MITF showed an opposite trend, i. e. the decrea- sed frequency of methylation and/or deletion. If dele- tions and/or methylation were not detected for any of the three down-regulated genes, one point was given for each gene in which methylation was not found (no point counts if changes were detected) in the sample [11]. Concluding, a comprehensive statistical analysis suggested a set of 19 gene markers for the early detec- tion, characteristics of tumor progression, prognosis of metastasizing, and for discrimination between SCC and ADC with sensitivity and specificity of 80–100 % (Tab- le 1, A–D) [11]. For detection of cancer cells in ovarian biopsies of all stages, including early one, the most perspective set from analyzed genes was the set of 8 biomarkers (Table 2, A) [16]. For discrimination between benign and malignant tumors it is possible to use the set of 8 biomarkers (Tab- le 2, B) [16]. To distinguish between stages I + II and stages III + + IV of ovarian cancer the most promising set should include 5 biomarkers (Table 2, C) [16]. Summarizing the obtained data, the set of 10 gene markers was developed for early detection and discrimi- nation of ovarian cancer groups with different histolo- gical characteristics [16]. 218 GORDIYUK V. V., KONDRATOV A. G., GERASHCHENKO A. V., KASHUBA V. I. Group Use Sets of markers A Detection of NSCLC IQSEC1, GORASP1/TTC21A, NKIRAS1/RPL15, RBSP3 (CTDSPL), LRRN1, ITGA9, FOXP1, TRH; Sp* = (95 ± 3) %; Sn** = (85 ± 6) %; P*** < 0.01 B Discrimination ADC and SCC NKIRAS1/RPL15, CGGBP1, VHL, LOC28375, EPHB1, BHLHE40, ANKRD28; Sp = (83 ± 11) %; Sn = (79 ± 8) %; P = 0.01 C Detection of metastases in ADC LRRC3B, UBE2E2, WNT7A, FGD5; Sp = 100 %; Sn = (80 ± 18) %; P = 0.02 D Detection of metastases in SCC GORAST1/TTC21A, LRRN1, VHL, MITF; Sp = (86 ± 13) %; Sn = (86 ± 8) %; P < 0.01 N o t e. Sp* – specificity; Sn** – sensitivity of the set; P*** – parameter shows significance of compared groups distinction, calculated using Fisher exact test and � 2 criteria. Table 1 Detection and discrimination of NSCLC groups with different histological characteristics, using the set of 19 selected genes Conclusions. Different types of epithelial tumors were analyzed, using the NotI microarray technology. We have found loci/genes with essential changes in ex- pression and methylation in a high proportion of tumor samples. Changes in the expression for several genes were confirmed, using the bisulfite sequencing (to mo- nitor changes in DNA methylation) and Q-PCR (to as- sess the relative level of gene expression). Thus, the NotI microarray technology allows the de- velopment of a panel of specific markers for the early detection of different tumor types as well as to discri- minate the stages of tumor growth and to determine whe- ther the tumor is metastasizing. The case study of lung and ovary tumors was a bright example of utility of marker panels that were crea- ted for detection of lung carcinoma, differentiation bet- ween adenocarcinoma and squamous lung carcinoma, and tumors with or without metastases. In the case of ovary carcinoma, the marker panels were created for early detection, discrimination of benign and malignant tumors, and also for discrimination of stages I + II vs stages III + IV. In sum, we developed a new approach to search for epigenetic markers of epithelial cancers. The presented results have a great perspective for their use in clinical medicine. Â. Â. Ãîðä³þê, Î. Ã. Êîíäðàòîâ, Ã. Â. Ãåðàùåíêî, Â. ². Êàøóáà Íîâ³ åï³ãåíåòè÷í³ ìàðêåðè ðàííüî¿ äåòåêö³¿ ïóõëèí åï³òåë³àëüíîãî ïîõîäæåííÿ òà ¿õ ïðîãíîçóâàííÿ Ðåçþìå  îãëÿä³ ðîçãëÿíóòî ãåíåòè÷í³ òà åï³ãåíåòè÷íèõ çì³íè, ÿê³ â³äáó- âàþòüñÿ ïðè óòâîðåíí³ ïóõëèí, òà ïîøóê ïåðñïåêòèâíèõ íàáîð³â íîâèõ á³îìàðêåð³â. Ïðåäñòàâëåíî äàí³ NotI-ì³êðî÷³ï³â äëÿ 3-¿ õðî- ìîñîìè ëþäèíè ùîäî çì³í ó ïóõëèíàõ íèðîê, øèéêè ìàòêè, òîâ- ñòîãî êèøå÷íèêà, ÿº÷íèê³â ³ ëåãåíü. Çíàéäåíî ëîêóñè/ãåíè ç ³ñòîò- íèìè çì³íàìè ìåòèëþâàííÿ ó çðàçêàõ ïóõëèí, ÿê³ ñóïðîâîäæóþòü- ñÿ çíèæåííÿì åêñïðåñ³¿ â³äïîâ³äíèõ ãåí³â. Ðåçóëüòàòè ì³êðî÷³ï³â âèêîðèñòàíî äëÿ ðîçðîáêè ïàíåëåé åï³ãåíåòè÷íèõ ìàðêåð³â ðàí- íüî¿ äåòåêö³¿ ð³çíèõ òèï³â ïóõëèí (ÿº÷íèê³â ³ ëåãåí³â), à òàêîæ äëÿ ðîçð³çíåííÿ ñòóïåí³â ïðîãðåñ³¿ ïóõëèí ³ âèÿâëåííÿ ìåòàñòàç³â. Ñòâîðåííÿ ïîä³áíèõ ïàíåëåé ìàðêåð³â º ïåðñïåêòèâíèì äëÿ çàñòî- ñóâàííÿ â êë³í³÷í³é ìåäèöèí³. Êëþ÷îâ³ ñëîâà: ïóõëèíè åï³òåë³àëüíîãî ïîõîäæåííÿ, åï³ãåíå- òè÷í³ ìàðêåðè, NotI-ì³êðî÷³ïè, ðàííÿ äåòåêö³ÿ ðàêó, ïðîãíîçóâàí- íÿ ðàêó, ãåíè – ñóïðåñîðè ðîñòó ïóõëèí. Â. Â. Ãîðäèþê, À. Ã. Êîíäðàòîâ, À. Â. Ãåðàùåíêî, Â. È. Êàøóáà Íîâûå ýïèãåíåòè÷åñêèå ìàðêåðû ðàííåé äèàãíîñòèêè îïóõîëåé ýïèòåëèàëüíîãî ïðîèñõîæäåíèÿ è èõ ïðîãíîçèðîâàíèÿ Ðåçþìå  îáçîðå ðàññìîòðåíû ãåíåòè÷åñêèå è ýïèãåíåòè÷åñêèå èçìåíå- íèÿ,ñîïóòñòâóþùèå îáðàçîâàíèþ îïóõîëåé, è ïîèñê ïåðñïåêòèâ- íûõ íàáîðîâ íîâûõ áèîìàðêåðîâ. Ïðåäñòàâëåíû äàííûå NotI-ìèê- ðî÷èïîâ äëÿ 3-é õðîìîñîìû ÷åëîâåêà îòíîñèòåëüíî èçìåíåíèé â îïóõîëÿõ ïî÷åê, øåéêè ìàòêè, òîëñòîãî êèøå÷íèêà, ÿè÷íèêîâ è ëåãêèõ. Íàéäåíû ëîêóñû/ãåíû ñ ñóùåñòâåííûìè èçìåíåíèÿìè ìå- òèëèðîâàíèÿ â îáðàçöàõ îïóõîëåé, ñîïðîâîæäàþùèìèñÿ ñíèæå- íèåì ýêñïðåññèè ñîîòâåòñòâóþùèõ ãåíîâ. Ðåçóëüòàòè ìèêðî÷è- ïîâ èñïîëüçîâàíû äëÿ ðàçðàáîòêè ïàíåëåé ýïèãåíåòè÷åñêèõ ìàð- êåðîâ ðàííåé äåòåêöèè ðàçíèõ òèïîâ îïóõîëåé (ÿè÷íèêîâ è ëåã- êèõ), à òàêæå äëÿ äèôôåðåíöèðîâàíèÿ ñòåïåíè ïðîãðåññèè îïó- õîëåé è âûÿâëåíèÿ ìåòàñòàçîâ. Ñîçäàíèå ïîäîáíûõ ïàíåëåé ìàð- êåðîâ ÿâëÿåòñÿ ïåðñïåêòèâíûì äëÿ ïðèìåíåíèÿ â êëèíè÷åñêîé ìå- äèöèíå. Êëþ÷åâûå ñëîâà: îïóõîëè ýïèòåëèàëüíîãî ïðîèñõîæäåíèÿ, ýïè- ãåíåòè÷åñêèå ìàðêåðû, NotI-ìèêðî÷èïè, ðàííÿÿ äåòåêöèÿ ðàêà, ïðîãíîçèðîâàíèå ðàêà, ãåíû – ñóïðåñîðû ðîñòà îïóõîëåé. REFERENCES 1. Li J., Protopopov A., Wang F. et al. NotI subtraction and NotI- specific microarrays to detect copy number and methylation changes in whole genomes // Proc. Natl Acad. Sci. USA.– 2002.–99, N 16.–P. 10724–10729. 2. Kutsenko A. S., Gizatullin R. Z., Al-Amin A. N. et al. 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