Array-Based Comparative Genomic Hybridization Identifies CDK4 and FOXM1 Alterations as Independent Predictors of Survival in Malignant Peripheral Nerve Sheath Tumor
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCG...
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| Veröffentlicht in: | Clinical cancer research 2011-04, Vol.17 (7), p.1924-1934 |
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| creator | JINSHENG YU DESHMUKH, Hrishikesh LINDBERG, Guy M GUTMANN, Rebecca J EMNETT, Ryan J SALAVAGGIONE, Lorena GUTMANN, David H NAGARAJAN, Rakesh WATSON, Mark A PERRY, Arie PAYTON, Jacqueline E DUNHAM, Christopher SCHEITHAUER, Bernd W TIHAN, Tarik PRAYSON, Richard A GUHA, Abhijit BRIDGE, Julia A FERNER, Rosalie E |
| description | Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs.
Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens.
aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05).
Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients. |
| doi_str_mv | 10.1158/1078-0432.ccr-10-1551 |
| format | Article |
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Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens.
aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05).
Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.ccr-10-1551</identifier><identifier>PMID: 21325289</identifier><identifier>CODEN: CCREF4</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adolescent ; Adult ; Aged ; Antineoplastic agents ; Biological and medical sciences ; Biomarkers, Tumor - genetics ; Child ; Comparative Genomic Hybridization ; Cyclin-Dependent Kinase 4 - genetics ; Female ; Forkhead Box Protein M1 ; Forkhead Transcription Factors - genetics ; Gene Dosage ; Gene Duplication ; Genetic Association Studies ; Humans ; In Situ Hybridization, Fluorescence ; Kaplan-Meier Estimate ; Male ; Medical sciences ; Membrane Proteins - genetics ; Middle Aged ; Multivariate Analysis ; Neoplasm Recurrence, Local ; Nerve Sheath Neoplasms - diagnosis ; Nerve Sheath Neoplasms - genetics ; Nerve Sheath Neoplasms - mortality ; Neurology ; Nuclear Proteins - genetics ; Pharmacology. Drug treatments ; Prognosis ; Proportional Hazards Models ; Proto-Oncogene Proteins c-myc - genetics ; Receptor, ErbB-2 - genetics ; SOXD Transcription Factors - genetics ; Tacrolimus Binding Protein 1A - genetics ; Tetraspanins ; Transcription, Genetic ; tRNA Methyltransferases - genetics ; Tumor Suppressor Protein p53 - genetics ; Tumors of the nervous system. Phacomatoses ; Young Adult</subject><ispartof>Clinical cancer research, 2011-04, Vol.17 (7), p.1924-1934</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-42ce1980e08b807050ae43975c171c9fd106d4da4d37ba4cbec6660a0c2a25e3</citedby><cites>FETCH-LOGICAL-c451t-42ce1980e08b807050ae43975c171c9fd106d4da4d37ba4cbec6660a0c2a25e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,3357,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24043575$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21325289$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>JINSHENG YU</creatorcontrib><creatorcontrib>DESHMUKH, Hrishikesh</creatorcontrib><creatorcontrib>LINDBERG, Guy M</creatorcontrib><creatorcontrib>GUTMANN, Rebecca J</creatorcontrib><creatorcontrib>EMNETT, Ryan J</creatorcontrib><creatorcontrib>SALAVAGGIONE, Lorena</creatorcontrib><creatorcontrib>GUTMANN, David H</creatorcontrib><creatorcontrib>NAGARAJAN, Rakesh</creatorcontrib><creatorcontrib>WATSON, Mark A</creatorcontrib><creatorcontrib>PERRY, Arie</creatorcontrib><creatorcontrib>PAYTON, Jacqueline E</creatorcontrib><creatorcontrib>DUNHAM, Christopher</creatorcontrib><creatorcontrib>SCHEITHAUER, Bernd W</creatorcontrib><creatorcontrib>TIHAN, Tarik</creatorcontrib><creatorcontrib>PRAYSON, Richard A</creatorcontrib><creatorcontrib>GUHA, Abhijit</creatorcontrib><creatorcontrib>BRIDGE, Julia A</creatorcontrib><creatorcontrib>FERNER, Rosalie E</creatorcontrib><title>Array-Based Comparative Genomic Hybridization Identifies CDK4 and FOXM1 Alterations as Independent Predictors of Survival in Malignant Peripheral Nerve Sheath Tumor</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs.
Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens.
aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05).
Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Child</subject><subject>Comparative Genomic Hybridization</subject><subject>Cyclin-Dependent Kinase 4 - genetics</subject><subject>Female</subject><subject>Forkhead Box Protein M1</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Gene Dosage</subject><subject>Gene Duplication</subject><subject>Genetic Association Studies</subject><subject>Humans</subject><subject>In Situ Hybridization, Fluorescence</subject><subject>Kaplan-Meier Estimate</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Proteins - genetics</subject><subject>Middle Aged</subject><subject>Multivariate Analysis</subject><subject>Neoplasm Recurrence, Local</subject><subject>Nerve Sheath Neoplasms - diagnosis</subject><subject>Nerve Sheath Neoplasms - genetics</subject><subject>Nerve Sheath Neoplasms - mortality</subject><subject>Neurology</subject><subject>Nuclear Proteins - genetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Prognosis</subject><subject>Proportional Hazards Models</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>SOXD Transcription Factors - genetics</subject><subject>Tacrolimus Binding Protein 1A - genetics</subject><subject>Tetraspanins</subject><subject>Transcription, Genetic</subject><subject>tRNA Methyltransferases - genetics</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumors of the nervous system. Phacomatoses</subject><subject>Young Adult</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkUFv1DAQhS0EoqXwE0C-IE4ptmMn2eMSaLuipYjugVs0sSesUWIHO1lp-T38UJx2C6cZjb73RnqPkNecnXOuqveclVXGZC7OtQ4ZZxlXij8hp2mUWS4K9TTtj8wJeRHjT8a45Ew-JyeC50KJanVK_qxDgEP2ASIaWvthhACT3SO9ROcHq-nVoQ3W2N_p6h3dGHST7SxGWn_8LCk4Qy9uv99wuu4nDPdQpBDpxhkc0S04_RrQWD35EKnv6N0c9nYPPbWO3kBvfzhYGAx23CWHnn7BkP7f7RCmHd3Ogw8vybMO-oivjvOMbC8-beur7Pr2clOvrzMtFZ8yKTTyVcWQVW3FSqYYoMxXpdK85HrVGc4KIw1Ik5ctSN2iLoqCAdMChML8jLx7sB2D_zVjnJrBRo19Dw79HJuqKFOwTBSJVA-kDj7GgF0zBjtAODScNUs9zRJ9s0Tf1PW3-2uqJ-neHD_M7YDmn-qxjwS8PQIQNfRdAKdt_M_JZKlKlf8FzOaahQ</recordid><startdate>20110401</startdate><enddate>20110401</enddate><creator>JINSHENG YU</creator><creator>DESHMUKH, Hrishikesh</creator><creator>LINDBERG, Guy M</creator><creator>GUTMANN, Rebecca J</creator><creator>EMNETT, Ryan J</creator><creator>SALAVAGGIONE, Lorena</creator><creator>GUTMANN, David H</creator><creator>NAGARAJAN, Rakesh</creator><creator>WATSON, Mark A</creator><creator>PERRY, Arie</creator><creator>PAYTON, Jacqueline E</creator><creator>DUNHAM, Christopher</creator><creator>SCHEITHAUER, Bernd W</creator><creator>TIHAN, Tarik</creator><creator>PRAYSON, Richard A</creator><creator>GUHA, Abhijit</creator><creator>BRIDGE, Julia A</creator><creator>FERNER, Rosalie E</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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>7X8</scope></search><sort><creationdate>20110401</creationdate><title>Array-Based Comparative Genomic Hybridization Identifies CDK4 and FOXM1 Alterations as Independent Predictors of Survival in Malignant Peripheral Nerve Sheath Tumor</title><author>JINSHENG YU ; DESHMUKH, Hrishikesh ; LINDBERG, Guy M ; GUTMANN, Rebecca J ; EMNETT, Ryan J ; SALAVAGGIONE, Lorena ; GUTMANN, David H ; NAGARAJAN, Rakesh ; WATSON, Mark A ; PERRY, Arie ; PAYTON, Jacqueline E ; DUNHAM, Christopher ; SCHEITHAUER, Bernd W ; TIHAN, Tarik ; PRAYSON, Richard A ; GUHA, Abhijit ; BRIDGE, Julia A ; FERNER, Rosalie E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-42ce1980e08b807050ae43975c171c9fd106d4da4d37ba4cbec6660a0c2a25e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Child</topic><topic>Comparative Genomic Hybridization</topic><topic>Cyclin-Dependent Kinase 4 - genetics</topic><topic>Female</topic><topic>Forkhead Box Protein M1</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Gene Dosage</topic><topic>Gene Duplication</topic><topic>Genetic Association Studies</topic><topic>Humans</topic><topic>In Situ Hybridization, Fluorescence</topic><topic>Kaplan-Meier Estimate</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membrane Proteins - genetics</topic><topic>Middle Aged</topic><topic>Multivariate Analysis</topic><topic>Neoplasm Recurrence, Local</topic><topic>Nerve Sheath Neoplasms - diagnosis</topic><topic>Nerve Sheath Neoplasms - genetics</topic><topic>Nerve Sheath Neoplasms - mortality</topic><topic>Neurology</topic><topic>Nuclear Proteins - genetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Prognosis</topic><topic>Proportional Hazards Models</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>SOXD Transcription Factors - genetics</topic><topic>Tacrolimus Binding Protein 1A - genetics</topic><topic>Tetraspanins</topic><topic>Transcription, Genetic</topic><topic>tRNA Methyltransferases - genetics</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumors of the nervous system. Phacomatoses</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>JINSHENG YU</creatorcontrib><creatorcontrib>DESHMUKH, Hrishikesh</creatorcontrib><creatorcontrib>LINDBERG, Guy M</creatorcontrib><creatorcontrib>GUTMANN, Rebecca J</creatorcontrib><creatorcontrib>EMNETT, Ryan J</creatorcontrib><creatorcontrib>SALAVAGGIONE, Lorena</creatorcontrib><creatorcontrib>GUTMANN, David H</creatorcontrib><creatorcontrib>NAGARAJAN, Rakesh</creatorcontrib><creatorcontrib>WATSON, Mark A</creatorcontrib><creatorcontrib>PERRY, Arie</creatorcontrib><creatorcontrib>PAYTON, Jacqueline E</creatorcontrib><creatorcontrib>DUNHAM, Christopher</creatorcontrib><creatorcontrib>SCHEITHAUER, Bernd W</creatorcontrib><creatorcontrib>TIHAN, Tarik</creatorcontrib><creatorcontrib>PRAYSON, Richard A</creatorcontrib><creatorcontrib>GUHA, Abhijit</creatorcontrib><creatorcontrib>BRIDGE, Julia A</creatorcontrib><creatorcontrib>FERNER, Rosalie E</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>JINSHENG YU</au><au>DESHMUKH, Hrishikesh</au><au>LINDBERG, Guy M</au><au>GUTMANN, Rebecca J</au><au>EMNETT, Ryan J</au><au>SALAVAGGIONE, Lorena</au><au>GUTMANN, David H</au><au>NAGARAJAN, Rakesh</au><au>WATSON, Mark A</au><au>PERRY, Arie</au><au>PAYTON, Jacqueline E</au><au>DUNHAM, Christopher</au><au>SCHEITHAUER, Bernd W</au><au>TIHAN, Tarik</au><au>PRAYSON, Richard A</au><au>GUHA, Abhijit</au><au>BRIDGE, Julia A</au><au>FERNER, Rosalie E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Array-Based Comparative Genomic Hybridization Identifies CDK4 and FOXM1 Alterations as Independent Predictors of Survival in Malignant Peripheral Nerve Sheath Tumor</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2011-04-01</date><risdate>2011</risdate><volume>17</volume><issue>7</issue><spage>1924</spage><epage>1934</epage><pages>1924-1934</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><coden>CCREF4</coden><abstract>Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs.
Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens.
aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05).
Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>21325289</pmid><doi>10.1158/1078-0432.ccr-10-1551</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| issn | 1078-0432 1557-3265 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | Adolescent Adult Aged Antineoplastic agents Biological and medical sciences Biomarkers, Tumor - genetics Child Comparative Genomic Hybridization Cyclin-Dependent Kinase 4 - genetics Female Forkhead Box Protein M1 Forkhead Transcription Factors - genetics Gene Dosage Gene Duplication Genetic Association Studies Humans In Situ Hybridization, Fluorescence Kaplan-Meier Estimate Male Medical sciences Membrane Proteins - genetics Middle Aged Multivariate Analysis Neoplasm Recurrence, Local Nerve Sheath Neoplasms - diagnosis Nerve Sheath Neoplasms - genetics Nerve Sheath Neoplasms - mortality Neurology Nuclear Proteins - genetics Pharmacology. Drug treatments Prognosis Proportional Hazards Models Proto-Oncogene Proteins c-myc - genetics Receptor, ErbB-2 - genetics SOXD Transcription Factors - genetics Tacrolimus Binding Protein 1A - genetics Tetraspanins Transcription, Genetic tRNA Methyltransferases - genetics Tumor Suppressor Protein p53 - genetics Tumors of the nervous system. Phacomatoses Young Adult |
| title | Array-Based Comparative Genomic Hybridization Identifies CDK4 and FOXM1 Alterations as Independent Predictors of Survival in Malignant Peripheral Nerve Sheath Tumor |
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