{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T07:41:21Z","timestamp":1777102881155,"version":"3.51.4"},"reference-count":27,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,8,9]],"date-time":"2019-08-09T00:00:00Z","timestamp":1565308800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002704","name":"Fundaci\u00f3n Cient\u00edfica Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer","doi-asserted-by":"publisher","award":["AIO 15152858"],"award-info":[{"award-number":["AIO 15152858"]}],"id":[{"id":"10.13039\/501100002704","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Institute of Health Carlos III","doi-asserted-by":"publisher","award":["PI17\u201000883"],"award-info":[{"award-number":["PI17\u201000883"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Spanish Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministry of Science, Innovation and Universities","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["RETOS RTI2018\u2010095039\u2010B\u2010I00"],"award-info":[{"award-number":["RETOS RTI2018\u2010095039\u2010B\u2010I00"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:p>The mammalian target of rapamycin (mTOR) pathway inhibitors are key drugs for the treatment of many tumor types, however, there are no predictive biomarkers in clinical use. Here, we performed a molecular and immunohistochemical characterization of key mTOR pathway components in a series of 105 renal cell carcinoma patients treated with rapalogs, aimed at identifying markers of treatment response. Mutational analysis in <jats:italic>MTOR<\/jats:italic>, <jats:italic>TSC1<\/jats:italic> and <jats:italic>TSC2<\/jats:italic> was performed through targeted next\u2010generation sequencing (NGS), and immunohistochemistry (IHC) was performed for PTEN, pAKT, pS6K1, pS6 and p21. Among patients with NGS data, 11 of 87 (13%) had mTOR pathway mutations (8 in <jats:italic>MTOR<\/jats:italic>, 1 in <jats:italic>TSC1<\/jats:italic> and 2 in <jats:italic>TSC2<\/jats:italic>). When comparing the molecular data to the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (odds ratio [OR] = 0.08, 95% confidence interval [CI] = 0.008\u20130.79, <jats:italic>p<\/jats:italic> = 0.030 univariate; <jats:italic>p<\/jats:italic> = 0.038 multivariable). Regarding IHC, negative PTEN staining was detected in 58% of the tumors, and it was more frequent in rapalog responder patients (OR = 0.24, 95% CI = 0.065\u20130.86, <jats:italic>p<\/jats:italic> = 0.029 univariate; <jats:italic>p<\/jats:italic> = 0.029 multivariable). Mutations and PTEN IHC were not mutually exclusive events and its combination improved response prediction (OR = 0.16, 95% CI = 0.04\u20130.62, <jats:italic>p<\/jats:italic> = 0.008 univariate; <jats:italic>p<\/jats:italic> = 0.013 multivariable). The staining of other proteins did not show and association with response and no association with PFS was observed in unselected patients. In conclusion, our findings suggest that mTOR pathway mutations, negative PTEN IHC and their combination are potential markers of rapalog response.<\/jats:p>","DOI":"10.1002\/ijc.32579","type":"journal-article","created":{"date-parts":[[2019,7,23]],"date-time":"2019-07-23T16:36:15Z","timestamp":1563899775000},"page":"1435-1444","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["PTEN expression and mutations in <i>TSC1<\/i>, <i>TSC2<\/i> and <i>MTOR<\/i> are associated with response to rapalogs in patients with renal cell carcinoma"],"prefix":"10.1002","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5651-4313","authenticated-orcid":false,"given":"Juan M.","family":"Roldan\u2010Romero","sequence":"first","affiliation":[{"name":"Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO)  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benoit","family":"Beuselinck","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Oncology, Department of Oncology University of Leuven  Leuven Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Santos","sequence":"additional","affiliation":[{"name":"Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO)  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan F.","family":"Rodriguez\u2010Moreno","sequence":"additional","affiliation":[{"name":"Genitourinary and Gynecological Cancer Unit HM Hospitales \u2013 Centro Integral Oncol\u00f3gico HM Clara Campal  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Lanillos","sequence":"additional","affiliation":[{"name":"Hereditary Endocrine Cancer Group, Human Cancer Genetics 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Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Puente","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Hospital Cl\u00ednico San Carlos, Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos (IdISSC), CIBERONC  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Castellano","sequence":"additional","affiliation":[{"name":"Hospital Universitario Doce de Octubre  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilio","family":"Esteban","sequence":"additional","affiliation":[{"name":"Hospital Central de Asturias  Oviedo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel A.","family":"Climent","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Instituto Valenciano de Oncologia  Valencia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose A.","family":"Arranz","sequence":"additional","affiliation":[{"name":"Hospital General Universitario Gregorio Mara\u00f1\u00f3n  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maarten","family":"Albersen","sequence":"additional","affiliation":[{"name":"Department of Urology University Hospitals Leuven  Leuven Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephane","family":"Oudard","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology H\u00f4pital Europ\u00e9en Georges\u2010Pompidou  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabrielle","family":"Couchy","sequence":"additional","affiliation":[{"name":"Inserm UMR 1162, Universit\u00e9 Paris\u2010Descartes  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Caleiras","sequence":"additional","affiliation":[{"name":"Histopathology Core Unit Spanish National Cancer Research Centre (CNIO)  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Montero\u2010Conde","sequence":"additional","affiliation":[{"name":"Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO)  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Casc\u00f3n","sequence":"additional","affiliation":[{"name":"Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO)  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER)  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Robledo","sequence":"additional","affiliation":[{"name":"Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO)  Madrid Spain"},{"name":"Centro de Investigaci\u00f3n 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