Cumulative Number of Altered Biomarkers in Mammalian Target of Rapamycin Pathway Is an Independent Predictor of Outcome in Patients With Clear Cell Renal Cell Carcinoma
Objective To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods Immunohistochemistry for phosphorylated-S6, phosphoryla...
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Veröffentlicht in: | Urology (Ridgewood, N.J.) N.J.), 2013-03, Vol.81 (3), p.581-586 |
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description | Objective To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. Results The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P = .01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P = .008). Conclusion The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC. |
doi_str_mv | 10.1016/j.urology.2012.11.030 |
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Materials and Methods Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. Results The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P = .01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P = .008). Conclusion The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.</description><identifier>ISSN: 0090-4295</identifier><identifier>EISSN: 1527-9995</identifier><identifier>DOI: 10.1016/j.urology.2012.11.030</identifier><identifier>PMID: 23290145</identifier><identifier>CODEN: URGYAZ</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biological and medical sciences ; Biomarkers, Tumor - analysis ; Biomarkers, Tumor - biosynthesis ; Carcinoma, Renal Cell - mortality ; Female ; Humans ; Kidney Neoplasms - mortality ; Kidneys ; Male ; Medical sciences ; Middle Aged ; Nephrology. Urinary tract diseases ; Prognosis ; Signal Transduction ; Survival Rate ; TOR Serine-Threonine Kinases - analysis ; TOR Serine-Threonine Kinases - biosynthesis ; Tumors of the urinary system ; Urology ; Young Adult</subject><ispartof>Urology (Ridgewood, N.J.), 2013-03, Vol.81 (3), p.581-586</ispartof><rights>Elsevier Inc.</rights><rights>2013 Elsevier Inc.</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c450t-d9be965a62aa2e9a93e779ecbca91554bffb302dfd33d37a23a40f136fda57633</citedby><cites>FETCH-LOGICAL-c450t-d9be965a62aa2e9a93e779ecbca91554bffb302dfd33d37a23a40f136fda57633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.urology.2012.11.030$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27178935$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23290145$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Darwish, Oussama M</creatorcontrib><creatorcontrib>Kapur, Payal</creatorcontrib><creatorcontrib>Youssef, Ramy F</creatorcontrib><creatorcontrib>Bagrodia, Aditya</creatorcontrib><creatorcontrib>Belsante, Michael</creatorcontrib><creatorcontrib>Alhalabi, Feras</creatorcontrib><creatorcontrib>Sagalowsky, Arthur I</creatorcontrib><creatorcontrib>Lotan, Yair</creatorcontrib><creatorcontrib>Margulis, Vitaly</creatorcontrib><title>Cumulative Number of Altered Biomarkers in Mammalian Target of Rapamycin Pathway Is an Independent Predictor of Outcome in Patients With Clear Cell Renal Cell Carcinoma</title><title>Urology (Ridgewood, N.J.)</title><addtitle>Urology</addtitle><description>Objective To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. Results The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P = .01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P = .008). Conclusion The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Biological and medical sciences</subject><subject>Biomarkers, Tumor - analysis</subject><subject>Biomarkers, Tumor - biosynthesis</subject><subject>Carcinoma, Renal Cell - mortality</subject><subject>Female</subject><subject>Humans</subject><subject>Kidney Neoplasms - mortality</subject><subject>Kidneys</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Prognosis</subject><subject>Signal Transduction</subject><subject>Survival Rate</subject><subject>TOR Serine-Threonine Kinases - analysis</subject><subject>TOR Serine-Threonine Kinases - biosynthesis</subject><subject>Tumors of the urinary system</subject><subject>Urology</subject><subject>Young Adult</subject><issn>0090-4295</issn><issn>1527-9995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkk1v1DAQhiMEokvhJ4B8QeKyiz_iBF9AJeJjpUKrUsTRmjiT1lsn3tpO0f4jfiYOu4DEhYttaZ55ZzzvFMVTRleMsurlZjUF7_zVbsUp4yvGVlTQe8WCSV4vlVLyfrGgVNFlyZU8Kh7FuKGUVlVVPyyOuOCKslIuih_NNEwOkr1D8nkaWgzE9-TEJQzYkbfWDxBuMERiR_IJhgGchZFcQrjCNJMXsIVhZ3L0HNL1d9iRdSSZWI8dbjEfYyLnWcqa5H9Jn03J-AHJPsPmeCTfbLomjUMIpEHnyAWO4PbPBkIWz108Lh704CI-OdzHxdf37y6bj8vTsw_r5uR0aUpJ07JTLapKQsUBOCpQAutaoWkNKCZl2fZ9Kyjv-k6ITtTABZS0Z6LqO5B1JcRx8WKvuw3-dsKY9GCjya3AiH6KmglW1rTiUmVU7lETfIwBe70NNs9rpxnVs0l6ow8m6dkkzZjOJuW8Z4cSUztg9yfrtysZeH4AIBpwfYDR2PiXq1n9SomZe7PnMA_kzmLQ0eSJmjzugCbpztv_tvL6HwXj7Ghz0RvcYdz4KWQr8q915JrqL_NGzQvFskjJeS1-Ak_WyhI</recordid><startdate>20130301</startdate><enddate>20130301</enddate><creator>Darwish, Oussama M</creator><creator>Kapur, Payal</creator><creator>Youssef, Ramy F</creator><creator>Bagrodia, Aditya</creator><creator>Belsante, Michael</creator><creator>Alhalabi, Feras</creator><creator>Sagalowsky, Arthur I</creator><creator>Lotan, Yair</creator><creator>Margulis, Vitaly</creator><general>Elsevier Inc</general><general>Elsevier</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>20130301</creationdate><title>Cumulative Number of Altered Biomarkers in Mammalian Target of Rapamycin Pathway Is an Independent Predictor of Outcome in Patients With Clear Cell Renal Cell Carcinoma</title><author>Darwish, Oussama M ; Kapur, Payal ; Youssef, Ramy F ; Bagrodia, Aditya ; Belsante, Michael ; Alhalabi, Feras ; Sagalowsky, Arthur I ; Lotan, Yair ; Margulis, Vitaly</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c450t-d9be965a62aa2e9a93e779ecbca91554bffb302dfd33d37a23a40f136fda57633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Biological and medical sciences</topic><topic>Biomarkers, Tumor - analysis</topic><topic>Biomarkers, Tumor - biosynthesis</topic><topic>Carcinoma, Renal Cell - mortality</topic><topic>Female</topic><topic>Humans</topic><topic>Kidney Neoplasms - mortality</topic><topic>Kidneys</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Prognosis</topic><topic>Signal Transduction</topic><topic>Survival Rate</topic><topic>TOR Serine-Threonine Kinases - analysis</topic><topic>TOR Serine-Threonine Kinases - biosynthesis</topic><topic>Tumors of the urinary system</topic><topic>Urology</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Darwish, Oussama M</creatorcontrib><creatorcontrib>Kapur, Payal</creatorcontrib><creatorcontrib>Youssef, Ramy F</creatorcontrib><creatorcontrib>Bagrodia, Aditya</creatorcontrib><creatorcontrib>Belsante, Michael</creatorcontrib><creatorcontrib>Alhalabi, Feras</creatorcontrib><creatorcontrib>Sagalowsky, Arthur I</creatorcontrib><creatorcontrib>Lotan, Yair</creatorcontrib><creatorcontrib>Margulis, Vitaly</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>Urology (Ridgewood, N.J.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Darwish, Oussama M</au><au>Kapur, Payal</au><au>Youssef, Ramy F</au><au>Bagrodia, Aditya</au><au>Belsante, Michael</au><au>Alhalabi, Feras</au><au>Sagalowsky, Arthur I</au><au>Lotan, Yair</au><au>Margulis, Vitaly</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cumulative Number of Altered Biomarkers in Mammalian Target of Rapamycin Pathway Is an Independent Predictor of Outcome in Patients With Clear Cell Renal Cell Carcinoma</atitle><jtitle>Urology (Ridgewood, N.J.)</jtitle><addtitle>Urology</addtitle><date>2013-03-01</date><risdate>2013</risdate><volume>81</volume><issue>3</issue><spage>581</spage><epage>586</epage><pages>581-586</pages><issn>0090-4295</issn><eissn>1527-9995</eissn><coden>URGYAZ</coden><abstract>Objective To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. Results The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P = .01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P = .008). Conclusion The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>23290145</pmid><doi>10.1016/j.urology.2012.11.030</doi><tpages>6</tpages></addata></record> |
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subjects | Adolescent Adult Aged Aged, 80 and over Biological and medical sciences Biomarkers, Tumor - analysis Biomarkers, Tumor - biosynthesis Carcinoma, Renal Cell - mortality Female Humans Kidney Neoplasms - mortality Kidneys Male Medical sciences Middle Aged Nephrology. Urinary tract diseases Prognosis Signal Transduction Survival Rate TOR Serine-Threonine Kinases - analysis TOR Serine-Threonine Kinases - biosynthesis Tumors of the urinary system Urology Young Adult |
title | Cumulative Number of Altered Biomarkers in Mammalian Target of Rapamycin Pathway Is an Independent Predictor of Outcome in Patients With Clear Cell Renal Cell Carcinoma |
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