Identification and Clinical Validation of a Novel 4 Gene-Signature with Prognostic Utility in Colorectal Cancer
Colorectal cancer (CRC) is a high burden disease with several genes involved in tumor progression. The aim of the present study was to identify, generate and clinically validate a novel gene signature to improve prediction of overall survival (OS) to effectively manage colorectal cancer. We explored...
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| Veröffentlicht in: | International journal of molecular sciences 2019-08, Vol.20 (15), p.3818 |
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| creator | Ahluwalia, Pankaj Mondal, Ashis K Bloomer, Chance Fulzele, Sadanand Jones, Kimya Ananth, Sudha Gahlay, Gagandeep K Heneidi, Saleh Rojiani, Amyn M Kota, Vamsi Kolhe, Ravindra |
| description | Colorectal cancer (CRC) is a high burden disease with several genes involved in tumor progression. The aim of the present study was to identify, generate and clinically validate a novel gene signature to improve prediction of overall survival (OS) to effectively manage colorectal cancer. We explored The Cancer Genome Atlas (TCGA), COAD and READ datasets (597 samples) from The Protein Atlas (TPA) database to extract a total of 595 candidate genes. In parallel, we identified 29 genes with perturbations in > 6 cancers which are also affected in CRC. These genes were entered in cBioportal to generate a 17 gene panel with highest perturbations. For clinical validation, this gene panel was tested on the FFPE tissues of colorectal cancer patients (88 patients) using Nanostring analysis. Using multivariate analysis, a high prognostic score (composite 4 gene signature-
,
,
and
) was found to be a significant predictor of poor prognosis in CRC patients (HR: 3.42, 95% CI: 1.71-7.94,
< 0.001 *) along with stage (HR: 4.56, 95% CI: 1.35-19.15,
= 0.01 *). The Kaplan-Meier analysis also segregated patients on the basis of prognostic score (log-rank test,
= 0.001 *). The external validation using GEO dataset (GSE38832, 122 patients) corroborated the prognostic score (HR: 2.7, 95% CI: 1.99-3.73,
< 0.001 *). Additionally, higher score was able to differentiate stage II and III patients (130 patients) on the basis of OS (HR: 2.5, 95% CI: 1.78-3.63,
< 0.001 *). Overall, our results identify a novel 4 gene prognostic signature that has clinical utility in colorectal cancer. |
| doi_str_mv | 10.3390/ijms20153818 |
| format | Article |
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,
,
and
) was found to be a significant predictor of poor prognosis in CRC patients (HR: 3.42, 95% CI: 1.71-7.94,
< 0.001 *) along with stage (HR: 4.56, 95% CI: 1.35-19.15,
= 0.01 *). The Kaplan-Meier analysis also segregated patients on the basis of prognostic score (log-rank test,
= 0.001 *). The external validation using GEO dataset (GSE38832, 122 patients) corroborated the prognostic score (HR: 2.7, 95% CI: 1.99-3.73,
< 0.001 *). Additionally, higher score was able to differentiate stage II and III patients (130 patients) on the basis of OS (HR: 2.5, 95% CI: 1.78-3.63,
< 0.001 *). Overall, our results identify a novel 4 gene prognostic signature that has clinical utility in colorectal cancer.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms20153818</identifier><identifier>PMID: 31387239</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Adenocarcinoma ; Age ; Aged ; Aged, 80 and over ; Alcohol ; Biomarkers ; Biomarkers, Tumor ; Colon ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - diagnosis ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - mortality ; Colorectal Neoplasms - therapy ; Combined Modality Therapy ; Datasets ; Ethnicity ; Family medical history ; Female ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Kaplan-Meier Estimate ; Male ; Medical prognosis ; Middle Aged ; Multivariate analysis ; Neoplasm Grading ; Neoplasm Metastasis ; Neoplasm Staging ; Patients ; Prognosis ; Proportional Hazards Models ; Regression analysis ; ROC Curve ; Statistical analysis ; Survival analysis ; Tobacco smoking ; Transcriptome</subject><ispartof>International journal of molecular sciences, 2019-08, Vol.20 (15), p.3818</ispartof><rights>2019. This work is licensed under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-df84797f65aac207acd0862d7d87ef6bfc6c510efd38269ebbc5e3af94d4160e3</citedby><cites>FETCH-LOGICAL-c412t-df84797f65aac207acd0862d7d87ef6bfc6c510efd38269ebbc5e3af94d4160e3</cites><orcidid>0000-0001-5621-3724 ; 0000-0002-0058-2827 ; 0000-0002-8283-2403 ; 0000-0003-3826-9489 ; 0000-0002-5290-9289</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/PMC6696416/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696416/$$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/31387239$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ahluwalia, Pankaj</creatorcontrib><creatorcontrib>Mondal, Ashis K</creatorcontrib><creatorcontrib>Bloomer, Chance</creatorcontrib><creatorcontrib>Fulzele, Sadanand</creatorcontrib><creatorcontrib>Jones, Kimya</creatorcontrib><creatorcontrib>Ananth, Sudha</creatorcontrib><creatorcontrib>Gahlay, Gagandeep K</creatorcontrib><creatorcontrib>Heneidi, Saleh</creatorcontrib><creatorcontrib>Rojiani, Amyn M</creatorcontrib><creatorcontrib>Kota, Vamsi</creatorcontrib><creatorcontrib>Kolhe, Ravindra</creatorcontrib><title>Identification and Clinical Validation of a Novel 4 Gene-Signature with Prognostic Utility in Colorectal Cancer</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Colorectal cancer (CRC) is a high burden disease with several genes involved in tumor progression. The aim of the present study was to identify, generate and clinically validate a novel gene signature to improve prediction of overall survival (OS) to effectively manage colorectal cancer. We explored The Cancer Genome Atlas (TCGA), COAD and READ datasets (597 samples) from The Protein Atlas (TPA) database to extract a total of 595 candidate genes. In parallel, we identified 29 genes with perturbations in > 6 cancers which are also affected in CRC. These genes were entered in cBioportal to generate a 17 gene panel with highest perturbations. For clinical validation, this gene panel was tested on the FFPE tissues of colorectal cancer patients (88 patients) using Nanostring analysis. Using multivariate analysis, a high prognostic score (composite 4 gene signature-
,
,
and
) was found to be a significant predictor of poor prognosis in CRC patients (HR: 3.42, 95% CI: 1.71-7.94,
< 0.001 *) along with stage (HR: 4.56, 95% CI: 1.35-19.15,
= 0.01 *). The Kaplan-Meier analysis also segregated patients on the basis of prognostic score (log-rank test,
= 0.001 *). The external validation using GEO dataset (GSE38832, 122 patients) corroborated the prognostic score (HR: 2.7, 95% CI: 1.99-3.73,
< 0.001 *). Additionally, higher score was able to differentiate stage II and III patients (130 patients) on the basis of OS (HR: 2.5, 95% CI: 1.78-3.63,
< 0.001 *). Overall, our results identify a novel 4 gene prognostic signature that has clinical utility in colorectal cancer.</description><subject>Adenocarcinoma</subject><subject>Age</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alcohol</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor</subject><subject>Colon</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - diagnosis</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - mortality</subject><subject>Colorectal Neoplasms - therapy</subject><subject>Combined Modality Therapy</subject><subject>Datasets</subject><subject>Ethnicity</subject><subject>Family medical history</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Kaplan-Meier Estimate</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Middle Aged</subject><subject>Multivariate analysis</subject><subject>Neoplasm Grading</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasm Staging</subject><subject>Patients</subject><subject>Prognosis</subject><subject>Proportional Hazards Models</subject><subject>Regression analysis</subject><subject>ROC Curve</subject><subject>Statistical analysis</subject><subject>Survival analysis</subject><subject>Tobacco smoking</subject><subject>Transcriptome</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkUtLHTEYhoO0eKs71yXgpgtHc5nJzGyEMrRWEBVauw05yZdjDjmJTTIW_31TjpVjV7k9PF9eXoSOKTnjfCTnbrXOjNCOD3TYQfu0ZawhRPTvtvZ76CDnFSGMs27cRXuc8qFnfNxH8cpAKM46rYqLAatg8ORdqGePfyrvzOY-WqzwTXwCj1t8CQGa724ZVJkT4N-uPOC7FJch5uI0vi_Ou_KMXcBT9DGBLlU2qaAhfUDvrfIZjl7WQ3T_9cuP6VtzfXt5NX2-bnRLWWmMHdp-7K3olNKM9EobMghmejP0YMXCaqE7SsAaPjAxwmKhO-DKjq1pqSDAD9HFxvs4L9ZgdA2ZlJePya1VepZROfn2JbgHuYxPUohRVEUVfHoRpPhrhlzk2mUN3qsAcc6S1bEtYT0bKnryH7qKcwo1nmScc8G6jvJKnW4onWLOCezrZyiRf5uU201W_ON2gFf4X3X8DxrIm74</recordid><startdate>20190805</startdate><enddate>20190805</enddate><creator>Ahluwalia, Pankaj</creator><creator>Mondal, Ashis K</creator><creator>Bloomer, Chance</creator><creator>Fulzele, Sadanand</creator><creator>Jones, Kimya</creator><creator>Ananth, Sudha</creator><creator>Gahlay, Gagandeep K</creator><creator>Heneidi, Saleh</creator><creator>Rojiani, Amyn M</creator><creator>Kota, Vamsi</creator><creator>Kolhe, Ravindra</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5621-3724</orcidid><orcidid>https://orcid.org/0000-0002-0058-2827</orcidid><orcidid>https://orcid.org/0000-0002-8283-2403</orcidid><orcidid>https://orcid.org/0000-0003-3826-9489</orcidid><orcidid>https://orcid.org/0000-0002-5290-9289</orcidid></search><sort><creationdate>20190805</creationdate><title>Identification and Clinical Validation of a Novel 4 Gene-Signature with Prognostic Utility in Colorectal Cancer</title><author>Ahluwalia, Pankaj ; Mondal, Ashis K ; Bloomer, Chance ; Fulzele, Sadanand ; Jones, Kimya ; Ananth, Sudha ; Gahlay, Gagandeep K ; Heneidi, Saleh ; Rojiani, Amyn M ; Kota, Vamsi ; Kolhe, Ravindra</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-df84797f65aac207acd0862d7d87ef6bfc6c510efd38269ebbc5e3af94d4160e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adenocarcinoma</topic><topic>Age</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alcohol</topic><topic>Biomarkers</topic><topic>Biomarkers, Tumor</topic><topic>Colon</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - diagnosis</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - mortality</topic><topic>Colorectal Neoplasms - therapy</topic><topic>Combined Modality Therapy</topic><topic>Datasets</topic><topic>Ethnicity</topic><topic>Family medical history</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Kaplan-Meier Estimate</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Middle Aged</topic><topic>Multivariate analysis</topic><topic>Neoplasm Grading</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Staging</topic><topic>Patients</topic><topic>Prognosis</topic><topic>Proportional Hazards Models</topic><topic>Regression analysis</topic><topic>ROC Curve</topic><topic>Statistical analysis</topic><topic>Survival analysis</topic><topic>Tobacco smoking</topic><topic>Transcriptome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ahluwalia, Pankaj</creatorcontrib><creatorcontrib>Mondal, Ashis K</creatorcontrib><creatorcontrib>Bloomer, Chance</creatorcontrib><creatorcontrib>Fulzele, Sadanand</creatorcontrib><creatorcontrib>Jones, Kimya</creatorcontrib><creatorcontrib>Ananth, Sudha</creatorcontrib><creatorcontrib>Gahlay, Gagandeep K</creatorcontrib><creatorcontrib>Heneidi, Saleh</creatorcontrib><creatorcontrib>Rojiani, Amyn M</creatorcontrib><creatorcontrib>Kota, Vamsi</creatorcontrib><creatorcontrib>Kolhe, Ravindra</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>MEDLINE - Academic</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>Ahluwalia, Pankaj</au><au>Mondal, Ashis K</au><au>Bloomer, Chance</au><au>Fulzele, Sadanand</au><au>Jones, Kimya</au><au>Ananth, Sudha</au><au>Gahlay, Gagandeep K</au><au>Heneidi, Saleh</au><au>Rojiani, Amyn M</au><au>Kota, Vamsi</au><au>Kolhe, Ravindra</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification and Clinical Validation of a Novel 4 Gene-Signature with Prognostic Utility in Colorectal Cancer</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2019-08-05</date><risdate>2019</risdate><volume>20</volume><issue>15</issue><spage>3818</spage><pages>3818-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Colorectal cancer (CRC) is a high burden disease with several genes involved in tumor progression. The aim of the present study was to identify, generate and clinically validate a novel gene signature to improve prediction of overall survival (OS) to effectively manage colorectal cancer. We explored The Cancer Genome Atlas (TCGA), COAD and READ datasets (597 samples) from The Protein Atlas (TPA) database to extract a total of 595 candidate genes. In parallel, we identified 29 genes with perturbations in > 6 cancers which are also affected in CRC. These genes were entered in cBioportal to generate a 17 gene panel with highest perturbations. For clinical validation, this gene panel was tested on the FFPE tissues of colorectal cancer patients (88 patients) using Nanostring analysis. Using multivariate analysis, a high prognostic score (composite 4 gene signature-
,
,
and
) was found to be a significant predictor of poor prognosis in CRC patients (HR: 3.42, 95% CI: 1.71-7.94,
< 0.001 *) along with stage (HR: 4.56, 95% CI: 1.35-19.15,
= 0.01 *). The Kaplan-Meier analysis also segregated patients on the basis of prognostic score (log-rank test,
= 0.001 *). The external validation using GEO dataset (GSE38832, 122 patients) corroborated the prognostic score (HR: 2.7, 95% CI: 1.99-3.73,
< 0.001 *). Additionally, higher score was able to differentiate stage II and III patients (130 patients) on the basis of OS (HR: 2.5, 95% CI: 1.78-3.63,
< 0.001 *). Overall, our results identify a novel 4 gene prognostic signature that has clinical utility in colorectal cancer.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>31387239</pmid><doi>10.3390/ijms20153818</doi><orcidid>https://orcid.org/0000-0001-5621-3724</orcidid><orcidid>https://orcid.org/0000-0002-0058-2827</orcidid><orcidid>https://orcid.org/0000-0002-8283-2403</orcidid><orcidid>https://orcid.org/0000-0003-3826-9489</orcidid><orcidid>https://orcid.org/0000-0002-5290-9289</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adenocarcinoma Age Aged Aged, 80 and over Alcohol Biomarkers Biomarkers, Tumor Colon Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - diagnosis Colorectal Neoplasms - genetics Colorectal Neoplasms - mortality Colorectal Neoplasms - therapy Combined Modality Therapy Datasets Ethnicity Family medical history Female Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Kaplan-Meier Estimate Male Medical prognosis Middle Aged Multivariate analysis Neoplasm Grading Neoplasm Metastasis Neoplasm Staging Patients Prognosis Proportional Hazards Models Regression analysis ROC Curve Statistical analysis Survival analysis Tobacco smoking Transcriptome |
| title | Identification and Clinical Validation of a Novel 4 Gene-Signature with Prognostic Utility in Colorectal Cancer |
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