Prognostic Significance of Biallelic Loss of PTEN in Clear Cell Renal Cell Carcinoma

No AccessJournal of UrologyInvestigative Urology1 Sep 2014Prognostic Significance of Biallelic Loss of PTEN in Clear Cell Renal Cell Carcinoma Hee Jin Lee, Ho Yun Lee, Jeong Hee Lee, Hajeong Lee, Guhyun Kang, Joon Seon Song, Jun Kang, and Ju Han Kim Hee Jin LeeHee Jin Lee Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea More articles by this author , Ho Yun LeeHo Yun Lee Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Financial interest and/or other relationship with Samsung Electronics. More articles by this author , Jeong Hee LeeJeong Hee Lee Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea More articles by this author , Hajeong LeeHajeong Lee Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea More articles by this author , Guhyun KangGuhyun Kang Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Inje University Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea More articles by this author , Joon Seon SongJoon Seon Song Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea More articles by this author , Jun KangJun Kang Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Inchun St. Mary's Hospital, Catholic University of Korea, Inchun, Republic of Korea More articles by this author , and Ju Han KimJu Han Kim Systems Biomedical Informatics National Core Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea Division of Biomedical Informatics, Seoul National University Biomedical Informatics, Seoul, Republic of Korea More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.03.097AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We investigated the clinical implications of biallelic loss of PTEN in clear cell renal cell carcinoma and whether PTEN biallelic loss would induce p53 dependent cellular senescence. Materials and Methods: Data were obtained using the CGDS-R package from the TCGA data set kirc_tcga_pub. PTEN allelic status was classified into 3 groups, including biallelic PTEN loss (homozygous deletion or combined heterozygous deletion and mutation), monoallelic PTEN loss (heterozygous deletion or mutation) and absent allelic loss. Univariate and multivariate overall survival analysis was performed. TP53 allelic loss and mean expression of genes related to p53 dependent cellular senescence were compared. Results: Of 416 patients with clear cell renal cell carcinoma 11 (2.6%) had biallelic PTEN loss and 69 (16.6%) had monoallelic loss. PTEN allelic loss was associated with late tumor stage and high histological grade. Patients with biallelic loss showed worse overall survival after adjusting for age and AJCC tumor stage (HR 3.1, 95% CI 1.4–6.8, p = 0.005). About half of the patients with PTEN biallelic loss had accompanying TP53 allelic loss. Biallelic loss of PTEN did not increase the expression of genes related to p53 dependent cellular senescence. Conclusions: PTEN biallelic loss may be a prognostic marker for clear cell renal cell carcinoma. It does not seem to induce p53 dependent cellular senescence, partly due to allelic loss of TP53. References 1 : Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res2013; 19: 3259. Google Scholar 2 : Intragenic PTEN/MMAC1 loss of heterozygosity in conventional (clear-cell) renal cell carcinoma is associated with poor patient prognosis. Mod Pathol2002; 15: 479. Google Scholar 3 : Somatic mutation and homozygous deletion of PTEN/MMAC1 gene of 10q23 in renal cell carcinoma. Anticancer Res1999; 19: 3841. Google Scholar 4 : PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. Int J Cancer2001; 91: 219. Google Scholar 5 : Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature2013; 499: 43. Google Scholar 6 : Haplo-insufficiency: a driving force in cancer. J Pathol2011; 223: 137. Google Scholar 7 : Pten is essential for embryonic development and tumour suppression. Nat Genet1998; 19: 348. Google Scholar 8 : Subtle variations in Pten dose determine cancer susceptibility. Nat Genet2010; 42: 454. Google Scholar 9 : The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol2012; 13: 283. Google Scholar 10 : A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest2010; 120: 681. Google Scholar 11 : Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature2005; 436: 725. Google Scholar 12 : Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform2013; 14: 178. Google Scholar 13 : Integrative genomics viewer. Nat Biotechnol2011; 29: 24. Google Scholar 14 : GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol2011; 12: R41. Google Scholar 15 : RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics2011; 12: 323. Google Scholar 16 : RNA-Seq gene expression estimation with read mapping uncertainty. Bioinformatics2010; 26: 493. Google Scholar 17 : MapSplice: accurate mapping of RNA-seq reads for splice junction discovery. Nucleic Acids Res2010; 38: e178. Google Scholar 18 : Reverse phase protein array: validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells. Mol Cancer Ther2006; 5: 2512. Google Scholar 19 : Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res2011; 39: e118. Google Scholar 20 : The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov2012; 2: 401. Google Scholar 21 : Multilevel whole-genome analysis reveals candidate biomarkers in clear cell renal cell carcinoma. Cancer Res2012; 72: 5273. Google Scholar 22 : Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer. J Urol2013; 190: 1990. Link, Google Scholar © 2014 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 192Issue 3September 2014Page: 940-946Supplementary Materials Advertisement Copyright & Permissions© 2014 by American Urological Association Education and Research, Inc.KeywordscarcinomaPTEN proteinhaploinsufficiencykidneyhumanrenal cellhigh-throughput nucleotide sequencingAcknowledgmentCommittee members and teachers of Certified Physicians in BioMedical Informatics provided support and assistance with this study.Metrics Author Information Hee Jin Lee Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea More articles by this author Ho Yun Lee Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Financial interest and/or other relationship with Samsung Electronics. More articles by this author Jeong Hee Lee Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea More articles by this author Hajeong Lee Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea More articles by this author Guhyun Kang Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Inje University Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea More articles by this author Joon Seon Song Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea More articles by this author Jun Kang Program for Certified Physicians in BioMedical Informatics, Korean Society of Medical Informatics, Seoul, Republic of Korea Department of Pathology, Inchun St. Mary's Hospital, Catholic University of Korea, Inchun, Republic of Korea More articles by this author Ju Han Kim Systems Biomedical Informatics National Core Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea Division of Biomedical Informatics, Seoul National University Biomedical Informatics, Seoul, Republic of Korea More articles by this author Expand All Advertisement PDF downloadLoading ...