Monosomy 3 Influences Epithelial-Mesenchymal Transition Gene Expression in Uveal Melanoma Patients; Consequences for Liquid Biopsy
Despite outstanding advances in diagnosis and the treatment of primary uveal melanoma (UM), nearly 50% of UM patients develop metastases via hematogenous dissemination, driven by the epithelial-mesenchymal transition (EMT). Despite the failure in UM to date, a liquid biopsy may offer a feasible non-...
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| Veröffentlicht in: | International journal of molecular sciences 2020-12, Vol.21 (24), p.9651 |
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| creator | Soltysova, Andrea Sedlackova, Tatiana Dvorska, Dana Jasek, Karin Chokhachi Baradaran, Pooneh Horvathova Kajabova, Viera Demkova, Lucia Buocikova, Verona Kurucova, Terezia Lyskova, Darina Furdova, Alena Minarik, Gabriel Babal, Pavel Dankova, Zuzana Smolkova, Bozena |
| description | Despite outstanding advances in diagnosis and the treatment of primary uveal melanoma (UM), nearly 50% of UM patients develop metastases via hematogenous dissemination, driven by the epithelial-mesenchymal transition (EMT). Despite the failure in UM to date, a liquid biopsy may offer a feasible non-invasive approach for monitoring metastatic disease progression and addressing protracted dormancy. To detect circulating tumor cells (CTCs) in UM patients, we evaluated the mRNA expression of EMT-associated transcription factors in CD45-depleted blood fraction, using qRT-PCR. ddPCR was employed to assess UM-specific
,
,
, and
mutations in plasma DNA. Moreover, microarray analysis was performed on total RNA isolated from tumor tissues to estimate the prognostic value of EMT-associated gene expression. In total, 42 primary UM and 11 metastatic patients were enrolled. All CD45-depleted samples were negative for CTC when compared to the peripheral blood fraction of 60 healthy controls. Tumor-specific mutations were detected in the plasma of 21.4% patients, merely, in 9.4% of primary UM, while 54.5% in metastatic patients. Unsupervised hierarchical clustering of differentially expressed EMT genes showed significant differences between monosomy 3 and disomy 3 tumors. Newly identified genes can serve as non-invasive prognostic biomarkers that can support therapeutic decisions. |
| doi_str_mv | 10.3390/ijms21249651 |
| format | Article |
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,
,
, and
mutations in plasma DNA. Moreover, microarray analysis was performed on total RNA isolated from tumor tissues to estimate the prognostic value of EMT-associated gene expression. In total, 42 primary UM and 11 metastatic patients were enrolled. All CD45-depleted samples were negative for CTC when compared to the peripheral blood fraction of 60 healthy controls. Tumor-specific mutations were detected in the plasma of 21.4% patients, merely, in 9.4% of primary UM, while 54.5% in metastatic patients. Unsupervised hierarchical clustering of differentially expressed EMT genes showed significant differences between monosomy 3 and disomy 3 tumors. Newly identified genes can serve as non-invasive prognostic biomarkers that can support therapeutic decisions.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21249651</identifier><identifier>PMID: 33348918</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Biomarkers ; Biomarkers, Tumor - genetics ; Biopsy ; Blood ; Cancer therapies ; Case-Control Studies ; CD45 antigen ; Cell adhesion & migration ; Chromosome Deletion ; Chromosomes ; Chromosomes, Human, Pair 3 - genetics ; Clustering ; Deoxyribonucleic acid ; Depletion ; DNA ; DNA microarrays ; DNA, Neoplasm - analysis ; DNA, Neoplasm - genetics ; Dormancy ; Epithelial-Mesenchymal Transition ; Female ; Follow-Up Studies ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes ; Humans ; Liquid Biopsy ; Male ; Medical prognosis ; Melanoma ; Melanoma - genetics ; Melanoma - secondary ; Melanoma - therapy ; Mesenchyme ; Metastases ; Metastasis ; Middle Aged ; Monosomy ; Mutation ; Neoplastic Cells, Circulating - metabolism ; Neoplastic Cells, Circulating - pathology ; Patients ; Peripheral blood ; Prognosis ; Proteins ; Transcription factors ; Tumor cells ; Tumors ; Uveal Neoplasms - genetics ; Uveal Neoplasms - secondary ; Uveal Neoplasms - therapy</subject><ispartof>International journal of molecular sciences, 2020-12, Vol.21 (24), p.9651</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-ad85697242956d6231879636e4f6f813630946dec53c4273e0d2c033c9154c2b3</citedby><cites>FETCH-LOGICAL-c412t-ad85697242956d6231879636e4f6f813630946dec53c4273e0d2c033c9154c2b3</cites><orcidid>0000-0001-8170-1850 ; 0000-0001-5689-892X ; 0000-0002-4906-5652 ; 0000-0002-2926-1664 ; 0000-0002-2466-9126 ; 0000-0002-7081-0602</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767066/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767066/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33348918$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Soltysova, Andrea</creatorcontrib><creatorcontrib>Sedlackova, Tatiana</creatorcontrib><creatorcontrib>Dvorska, Dana</creatorcontrib><creatorcontrib>Jasek, Karin</creatorcontrib><creatorcontrib>Chokhachi Baradaran, Pooneh</creatorcontrib><creatorcontrib>Horvathova Kajabova, Viera</creatorcontrib><creatorcontrib>Demkova, Lucia</creatorcontrib><creatorcontrib>Buocikova, Verona</creatorcontrib><creatorcontrib>Kurucova, Terezia</creatorcontrib><creatorcontrib>Lyskova, Darina</creatorcontrib><creatorcontrib>Furdova, Alena</creatorcontrib><creatorcontrib>Minarik, Gabriel</creatorcontrib><creatorcontrib>Babal, Pavel</creatorcontrib><creatorcontrib>Dankova, Zuzana</creatorcontrib><creatorcontrib>Smolkova, Bozena</creatorcontrib><title>Monosomy 3 Influences Epithelial-Mesenchymal Transition Gene Expression in Uveal Melanoma Patients; Consequences for Liquid Biopsy</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Despite outstanding advances in diagnosis and the treatment of primary uveal melanoma (UM), nearly 50% of UM patients develop metastases via hematogenous dissemination, driven by the epithelial-mesenchymal transition (EMT). Despite the failure in UM to date, a liquid biopsy may offer a feasible non-invasive approach for monitoring metastatic disease progression and addressing protracted dormancy. To detect circulating tumor cells (CTCs) in UM patients, we evaluated the mRNA expression of EMT-associated transcription factors in CD45-depleted blood fraction, using qRT-PCR. ddPCR was employed to assess UM-specific
,
,
, and
mutations in plasma DNA. Moreover, microarray analysis was performed on total RNA isolated from tumor tissues to estimate the prognostic value of EMT-associated gene expression. In total, 42 primary UM and 11 metastatic patients were enrolled. All CD45-depleted samples were negative for CTC when compared to the peripheral blood fraction of 60 healthy controls. Tumor-specific mutations were detected in the plasma of 21.4% patients, merely, in 9.4% of primary UM, while 54.5% in metastatic patients. Unsupervised hierarchical clustering of differentially expressed EMT genes showed significant differences between monosomy 3 and disomy 3 tumors. Newly identified genes can serve as non-invasive prognostic biomarkers that can support therapeutic decisions.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biopsy</subject><subject>Blood</subject><subject>Cancer therapies</subject><subject>Case-Control Studies</subject><subject>CD45 antigen</subject><subject>Cell adhesion & migration</subject><subject>Chromosome Deletion</subject><subject>Chromosomes</subject><subject>Chromosomes, Human, Pair 3 - genetics</subject><subject>Clustering</subject><subject>Deoxyribonucleic acid</subject><subject>Depletion</subject><subject>DNA</subject><subject>DNA microarrays</subject><subject>DNA, Neoplasm - analysis</subject><subject>DNA, Neoplasm - genetics</subject><subject>Dormancy</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Humans</subject><subject>Liquid Biopsy</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Melanoma</subject><subject>Melanoma - genetics</subject><subject>Melanoma - secondary</subject><subject>Melanoma - therapy</subject><subject>Mesenchyme</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Monosomy</subject><subject>Mutation</subject><subject>Neoplastic Cells, Circulating - metabolism</subject><subject>Neoplastic Cells, Circulating - pathology</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Transcription factors</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Uveal Neoplasms - genetics</subject><subject>Uveal Neoplasms - secondary</subject><subject>Uveal Neoplasms - therapy</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpVkc1v1DAQxS0Eoh9w44wscSVgexw7FhJSWS2l0q7g0J4t15mwXiV2amcr9spf3lRdquU0M56f3jzrEfKOs08Ahn0O26EILqRRNX9BTrkUomJM6ZdH_Qk5K2XLmABRm9fkBABkY3hzSv6uU0wlDXsK9Cp2_Q6jx0KXY5g22AfXV2ss89tmP7ieXmcXS5hCivQSI9LlnzFjKY9ziPTmHmdmjb2LaXD0l5sCxql8oYsUC94dpLuU6Src7UJLv4U0lv0b8qpzfcG3h3pObr4vrxc_qtXPy6vFxarykoupcm1TK6OFFKZWrRLAG20UKJSd6hoOCpiRqkVfg5dCA7JWeAbgDa-lF7dwTr4-6Y672wFbP3vLrrdjDoPLe5tcsP9vYtjY3-neaq00U2oW-HAQyGn-TZnsNu1ynD1bITU30AijZ-rjE-VzKiVj93yBM_uYmD1ObMbfH7t6hv9FBA8qmJOa</recordid><startdate>20201217</startdate><enddate>20201217</enddate><creator>Soltysova, Andrea</creator><creator>Sedlackova, Tatiana</creator><creator>Dvorska, Dana</creator><creator>Jasek, Karin</creator><creator>Chokhachi Baradaran, Pooneh</creator><creator>Horvathova Kajabova, Viera</creator><creator>Demkova, Lucia</creator><creator>Buocikova, Verona</creator><creator>Kurucova, Terezia</creator><creator>Lyskova, Darina</creator><creator>Furdova, Alena</creator><creator>Minarik, Gabriel</creator><creator>Babal, Pavel</creator><creator>Dankova, Zuzana</creator><creator>Smolkova, Bozena</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8170-1850</orcidid><orcidid>https://orcid.org/0000-0001-5689-892X</orcidid><orcidid>https://orcid.org/0000-0002-4906-5652</orcidid><orcidid>https://orcid.org/0000-0002-2926-1664</orcidid><orcidid>https://orcid.org/0000-0002-2466-9126</orcidid><orcidid>https://orcid.org/0000-0002-7081-0602</orcidid></search><sort><creationdate>20201217</creationdate><title>Monosomy 3 Influences Epithelial-Mesenchymal Transition Gene Expression in Uveal Melanoma Patients; Consequences for Liquid Biopsy</title><author>Soltysova, Andrea ; Sedlackova, Tatiana ; Dvorska, Dana ; Jasek, Karin ; Chokhachi Baradaran, Pooneh ; Horvathova Kajabova, Viera ; Demkova, Lucia ; Buocikova, Verona ; Kurucova, Terezia ; Lyskova, Darina ; Furdova, Alena ; Minarik, Gabriel ; Babal, Pavel ; Dankova, Zuzana ; Smolkova, Bozena</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-ad85697242956d6231879636e4f6f813630946dec53c4273e0d2c033c9154c2b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Biomarkers</topic><topic>Biomarkers, Tumor - 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metabolism</topic><topic>Neoplastic Cells, Circulating - pathology</topic><topic>Patients</topic><topic>Peripheral blood</topic><topic>Prognosis</topic><topic>Proteins</topic><topic>Transcription factors</topic><topic>Tumor cells</topic><topic>Tumors</topic><topic>Uveal Neoplasms - genetics</topic><topic>Uveal Neoplasms - secondary</topic><topic>Uveal Neoplasms - therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Soltysova, Andrea</creatorcontrib><creatorcontrib>Sedlackova, Tatiana</creatorcontrib><creatorcontrib>Dvorska, Dana</creatorcontrib><creatorcontrib>Jasek, Karin</creatorcontrib><creatorcontrib>Chokhachi Baradaran, Pooneh</creatorcontrib><creatorcontrib>Horvathova Kajabova, Viera</creatorcontrib><creatorcontrib>Demkova, Lucia</creatorcontrib><creatorcontrib>Buocikova, Verona</creatorcontrib><creatorcontrib>Kurucova, Terezia</creatorcontrib><creatorcontrib>Lyskova, Darina</creatorcontrib><creatorcontrib>Furdova, Alena</creatorcontrib><creatorcontrib>Minarik, Gabriel</creatorcontrib><creatorcontrib>Babal, Pavel</creatorcontrib><creatorcontrib>Dankova, Zuzana</creatorcontrib><creatorcontrib>Smolkova, Bozena</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Soltysova, Andrea</au><au>Sedlackova, Tatiana</au><au>Dvorska, Dana</au><au>Jasek, Karin</au><au>Chokhachi Baradaran, Pooneh</au><au>Horvathova Kajabova, Viera</au><au>Demkova, Lucia</au><au>Buocikova, Verona</au><au>Kurucova, Terezia</au><au>Lyskova, Darina</au><au>Furdova, Alena</au><au>Minarik, Gabriel</au><au>Babal, Pavel</au><au>Dankova, Zuzana</au><au>Smolkova, Bozena</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Monosomy 3 Influences Epithelial-Mesenchymal Transition Gene Expression in Uveal Melanoma Patients; Consequences for Liquid Biopsy</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2020-12-17</date><risdate>2020</risdate><volume>21</volume><issue>24</issue><spage>9651</spage><pages>9651-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Despite outstanding advances in diagnosis and the treatment of primary uveal melanoma (UM), nearly 50% of UM patients develop metastases via hematogenous dissemination, driven by the epithelial-mesenchymal transition (EMT). Despite the failure in UM to date, a liquid biopsy may offer a feasible non-invasive approach for monitoring metastatic disease progression and addressing protracted dormancy. To detect circulating tumor cells (CTCs) in UM patients, we evaluated the mRNA expression of EMT-associated transcription factors in CD45-depleted blood fraction, using qRT-PCR. ddPCR was employed to assess UM-specific
,
,
, and
mutations in plasma DNA. Moreover, microarray analysis was performed on total RNA isolated from tumor tissues to estimate the prognostic value of EMT-associated gene expression. In total, 42 primary UM and 11 metastatic patients were enrolled. All CD45-depleted samples were negative for CTC when compared to the peripheral blood fraction of 60 healthy controls. Tumor-specific mutations were detected in the plasma of 21.4% patients, merely, in 9.4% of primary UM, while 54.5% in metastatic patients. Unsupervised hierarchical clustering of differentially expressed EMT genes showed significant differences between monosomy 3 and disomy 3 tumors. Newly identified genes can serve as non-invasive prognostic biomarkers that can support therapeutic decisions.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33348918</pmid><doi>10.3390/ijms21249651</doi><orcidid>https://orcid.org/0000-0001-8170-1850</orcidid><orcidid>https://orcid.org/0000-0001-5689-892X</orcidid><orcidid>https://orcid.org/0000-0002-4906-5652</orcidid><orcidid>https://orcid.org/0000-0002-2926-1664</orcidid><orcidid>https://orcid.org/0000-0002-2466-9126</orcidid><orcidid>https://orcid.org/0000-0002-7081-0602</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1422-0067 |
| ispartof | International journal of molecular sciences, 2020-12, Vol.21 (24), p.9651 |
| issn | 1422-0067 1661-6596 1422-0067 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7767066 |
| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adult Aged Aged, 80 and over Biomarkers Biomarkers, Tumor - genetics Biopsy Blood Cancer therapies Case-Control Studies CD45 antigen Cell adhesion & migration Chromosome Deletion Chromosomes Chromosomes, Human, Pair 3 - genetics Clustering Deoxyribonucleic acid Depletion DNA DNA microarrays DNA, Neoplasm - analysis DNA, Neoplasm - genetics Dormancy Epithelial-Mesenchymal Transition Female Follow-Up Studies Gene expression Gene Expression Regulation, Neoplastic Genes Humans Liquid Biopsy Male Medical prognosis Melanoma Melanoma - genetics Melanoma - secondary Melanoma - therapy Mesenchyme Metastases Metastasis Middle Aged Monosomy Mutation Neoplastic Cells, Circulating - metabolism Neoplastic Cells, Circulating - pathology Patients Peripheral blood Prognosis Proteins Transcription factors Tumor cells Tumors Uveal Neoplasms - genetics Uveal Neoplasms - secondary Uveal Neoplasms - therapy |
| title | Monosomy 3 Influences Epithelial-Mesenchymal Transition Gene Expression in Uveal Melanoma Patients; Consequences for Liquid Biopsy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-06T09%3A41%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Monosomy%203%20Influences%20Epithelial-Mesenchymal%20Transition%20Gene%20Expression%20in%20Uveal%20Melanoma%20Patients;%20Consequences%20for%20Liquid%20Biopsy&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Soltysova,%20Andrea&rft.date=2020-12-17&rft.volume=21&rft.issue=24&rft.spage=9651&rft.pages=9651-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms21249651&rft_dat=%3Cproquest_pubme%3E2471938297%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2471938297&rft_id=info:pmid/33348918&rfr_iscdi=true |