{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T15:43:21Z","timestamp":1768319001855,"version":"3.49.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,7,7]],"date-time":"2016-07-07T00:00:00Z","timestamp":1467849600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,7,7]],"date-time":"2016-07-07T00:00:00Z","timestamp":1467849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bilateral renal cell carcinomas (RCCs) pose a challenge for clinical treatment and management. Most bilateral RCCs are sporadic, and do not show a hereditary pattern indicative of VHL syndrome or other inherited cancers. The origin and evolution of these sporadic bilateral RCCs remains elusive. We obtained normal and tumor samples from two male patients suffering from early stage synchronous bilateral clear cell RCC (ccRCC), and analyzed genomic DNA using whole exome sequencing and bisulfite pyrosequencing. We detected distinct 3p loss of heterozygosity (LOH) in both tumors in each patient. Two tumors within the same patient harbored distinct driver mutations and different CpG hypermethylation sites in the <jats:italic>VHL<\/jats:italic> promoter. Moreover, tumors exhibit independent evolutionary trajectories. Therefore, distinct 3p LOH, combined with contingent driver gene mutations and independent <jats:italic>VHL<\/jats:italic> hypermethylation, led to independent tumor origin and parallel evolution of bilateral ccRCC in these two patients. Our results indicate that tumors in these two cases were not due to common germline oncogenic mutations. They were results of multiple <jats:italic>de novo<\/jats:italic> mutations in each kidney, rather than primary ccRCC with contralateral renal metastasis. Therefore, histopathologic and genetic profiling from single tumor specimen may underestimate the mutational burden and somatic heterogeneity of bilateral ccRCCs.<\/jats:p>","DOI":"10.1038\/srep29267","type":"journal-article","created":{"date-parts":[[2016,7,7]],"date-time":"2016-07-07T09:39:38Z","timestamp":1467884378000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Independent Tumor Origin in Two Cases of Synchronous Bilateral Clear Cell Renal Cell Carcinoma"],"prefix":"10.1038","volume":"6","author":[{"given":"Zhengguo","family":"Ji","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuying","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haihong","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,7,7]]},"reference":[{"key":"BFsrep29267_CR1","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1016\/S0140-6736(09)60229-4","volume":"373","author":"BI Rini","year":"2009","unstructured":"Rini, B. I., Campbell, S. C. & Escudier, B. Renal cell carcinoma. Lancet 373, 1119\u20131132 (2009).","journal-title":"Lancet"},{"key":"BFsrep29267_CR2","doi-asserted-by":"publisher","first-page":"2893","DOI":"10.1002\/ijc.25516","volume":"127","author":"J Ferlay","year":"2010","unstructured":"Ferlay, J. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127, 2893\u20132917 (2010).","journal-title":"Int J Cancer"},{"key":"BFsrep29267_CR3","doi-asserted-by":"publisher","first-page":"3737","DOI":"10.1200\/JCO.2008.20.6524","volume":"27","author":"F Wiklund","year":"2009","unstructured":"Wiklund, F. et al. Risk of bilateral renal cell cancer. J Clin Oncol 27, 3737\u20133741 (2009).","journal-title":"J Clin Oncol"},{"key":"BFsrep29267_CR4","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1007\/BF02303649","volume":"5","author":"G Grimaldi","year":"1998","unstructured":"Grimaldi, G., Reuter, V. & Russo, P. Bilateral non-familial renal cell carcinoma. Ann Surg Oncol 5, 548\u2013552 (1998).","journal-title":"Ann Surg Oncol"},{"key":"BFsrep29267_CR5","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1111\/j.1464-410X.2009.08844.x","volume":"105","author":"WT Lowrance","year":"2010","unstructured":"Lowrance, W. T. et al. Developments in the surgical management of sporadic synchronous bilateral renal tumours. BJU Int 105, 1093\u20131097 (2010).","journal-title":"BJU Int"},{"key":"BFsrep29267_CR6","doi-asserted-by":"publisher","first-page":"2370","DOI":"10.1200\/JCO.2002.08.099","volume":"20","author":"F Rabbani","year":"2002","unstructured":"Rabbani, F., Herr, H. W., Almahmeed, T. & Russo, P. Temporal change in risk of metachronous contralateral renal cell carcinoma: influence of tumor characteristics and demographic factors. J Clin Oncol 20, 2370\u20132375 (2002).","journal-title":"J Clin Oncol"},{"key":"BFsrep29267_CR7","first-page":"562","volume":"45","author":"D Mu","year":"2013","unstructured":"Mu, D. et al. Prognostic and long term follow-up analysis of sporadic bilateral renal cell carcinoma. Journal of Peking Univeristy 45, 562\u2013566 (2013).","journal-title":"Journal of Peking Univeristy"},{"key":"BFsrep29267_CR8","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1111\/j.1464-410X.2007.06899.x","volume":"100","author":"S Pahernik","year":"2007","unstructured":"Pahernik, S., Cudovic, D., Roos, F., Melchior, S. W. & Thuroff, J. W. Bilateral synchronous sporadic renal cell carcinoma: surgical management, oncological and functional outcomes. BJU Int 100, 26\u201329 (2007).","journal-title":"BJU Int"},{"key":"BFsrep29267_CR9","doi-asserted-by":"crossref","unstructured":"Turajlic, S., Larkin, J. & Swanton, C. SnapShot: Renal Cell Carcinoma. Cell 163, 1556\u20131556 e1551 (2015).","DOI":"10.1016\/j.cell.2015.11.026"},{"key":"BFsrep29267_CR10","doi-asserted-by":"publisher","first-page":"5135","DOI":"10.1038\/ncomms6135","volume":"5","author":"G Scelo","year":"2014","unstructured":"Scelo, G. et al. Variation in genomic landscape of clear cell renal cell carcinoma across Europe. Nat Commun 5, 5135 (2014).","journal-title":"Nat Commun"},{"key":"BFsrep29267_CR11","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1038\/327721a0","volume":"327","author":"B Zbar","year":"1987","unstructured":"Zbar, B., Brauch, H., Talmadge, C. & Linehan, M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 327, 721\u2013724 (1987).","journal-title":"Nature"},{"key":"BFsrep29267_CR12","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1038\/ng.2699","volume":"45","author":"Y Sato","year":"2013","unstructured":"Sato, Y. et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 45, 860\u2013867 (2013).","journal-title":"Nat Genet"},{"key":"BFsrep29267_CR13","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/ng.2891","volume":"46","author":"M Gerlinger","year":"2014","unstructured":"Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet 46, 225\u2013233 (2014).","journal-title":"Nat Genet"},{"key":"BFsrep29267_CR14","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research, N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43\u201349 (2013).","DOI":"10.1038\/nature12222"},{"key":"BFsrep29267_CR15","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1002\/path.4214","volume":"230","author":"P Martinez","year":"2013","unstructured":"Martinez, P. et al. Parallel evolution of tumour subclones mimics diversity between tumours. J Pathol 230, 356\u2013364 (2013).","journal-title":"J Pathol"},{"key":"BFsrep29267_CR16","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1126\/science.8493574","volume":"260","author":"F Latif","year":"1993","unstructured":"Latif, F. et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260, 1317\u20131320 (1993).","journal-title":"Science"},{"key":"BFsrep29267_CR17","doi-asserted-by":"publisher","first-page":"4726","DOI":"10.1158\/1078-0432.CCR-07-4921","volume":"14","author":"ML Nickerson","year":"2008","unstructured":"Nickerson, M. L. et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 14, 4726\u20134734 (2008).","journal-title":"Clin Cancer Res"},{"key":"BFsrep29267_CR18","doi-asserted-by":"publisher","first-page":"e1002312","DOI":"10.1371\/journal.pgen.1002312","volume":"7","author":"LE Moore","year":"2011","unstructured":"Moore, L. E. et al. Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. PLoS Genet 7, e1002312 (2011).","journal-title":"PLoS Genet"},{"key":"BFsrep29267_CR19","doi-asserted-by":"publisher","first-page":"2081","DOI":"10.1016\/j.juro.2007.01.122","volume":"177","author":"T Klatte","year":"2007","unstructured":"Klatte, T. et al. Metachronous bilateral renal cell carcinoma: risk assessment, prognosis and relevance of the primary-free interval. J Urol 177, 2081\u20132086; discussion 2086\u20132087 (2007).","journal-title":"J Urol"},{"key":"BFsrep29267_CR20","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1186\/s13059-014-0433-z","volume":"15","author":"R Fisher","year":"2014","unstructured":"Fisher, R. et al. Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome Biol 15, 433 (2014).","journal-title":"Genome Biol"},{"key":"BFsrep29267_CR21","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1111\/j.1464-410X.2010.09561.x","volume":"107","author":"SK Hong","year":"2011","unstructured":"Hong, S. K. et al. Application of simplified Fuhrman grading system in clear-cell renal cell carcinoma. BJU Int 107, 409\u2013415 (2011).","journal-title":"BJU Int"},{"key":"BFsrep29267_CR22","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1002\/(SICI)1097-0142(19971101)80:9<1803::AID-CNCR16>3.0.CO;2-9","volume":"80","author":"LH Sobin","year":"1997","unstructured":"Sobin, L. H. & Fleming, I. D. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 80, 1803\u20131804 (1997).","journal-title":"Cancer"},{"key":"BFsrep29267_CR23","doi-asserted-by":"publisher","first-page":"D805","DOI":"10.1093\/nar\/gku1075","volume":"43","author":"SA Forbes","year":"2015","unstructured":"Forbes, S. A. et al. COSMIC: exploring the world\u2019s knowledge of somatic mutations in human cancer. Nucleic Acids Res 43, D805\u2013811 (2015).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep29267_CR24","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1038\/nrc2013","volume":"6","author":"LM Merlo","year":"2006","unstructured":"Merlo, L. M., Pepper, J. W., Reid, B. J. & Maley, C. C. Cancer as an evolutionary and ecological process. Nat Rev Cancer 6, 924\u2013935 (2006).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep29267_CR25","doi-asserted-by":"publisher","first-page":"10430","DOI":"10.1073\/pnas.190332597","volume":"97","author":"T Kamura","year":"2000","unstructured":"Kamura, T. et al. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA 97, 10430\u201310435 (2000).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep29267_CR26","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1038\/nature09144","volume":"465","author":"L Poliseno","year":"2010","unstructured":"Poliseno, L. et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033\u20131038 (2010).","journal-title":"Nature"},{"key":"BFsrep29267_CR27","doi-asserted-by":"publisher","first-page":"3086","DOI":"10.1158\/1535-7163.MCT-14-0245","volume":"13","author":"G Yu","year":"2014","unstructured":"Yu, G. et al. Pseudogene PTENP1 functions as a competing endogenous RNA to suppress clear-cell renal cell carcinoma progression. Mol Cancer Ther 13, 3086\u20133097 (2014).","journal-title":"Mol Cancer Ther"},{"key":"BFsrep29267_CR28","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1056\/NEJMoa1113205","volume":"366","author":"M Gerlinger","year":"2012","unstructured":"Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366, 883\u2013892 (2012).","journal-title":"N Engl J Med"},{"key":"BFsrep29267_CR29","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1002\/cam4.293","volume":"3","author":"A Sankin","year":"2014","unstructured":"Sankin, A. et al. The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling. Cancer Med 3, 1485\u20131492 (2014).","journal-title":"Cancer Med"},{"key":"BFsrep29267_CR30","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1016\/j.cell.2012.02.025","volume":"148","author":"X Xu","year":"2012","unstructured":"Xu, X. et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 148, 886\u2013895 (2012).","journal-title":"Cell"},{"key":"BFsrep29267_CR31","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1101\/gr.129684.111","volume":"22","author":"DC Koboldt","year":"2012","unstructured":"Koboldt, D. C. et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 22, 568\u2013576 (2012).","journal-title":"Genome Res"},{"key":"BFsrep29267_CR32","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1093\/biostatistics\/kxh008","volume":"5","author":"AB Olshen","year":"2004","unstructured":"Olshen, A. B., Venkatraman, E. S., Lucito, R. & Wigler, M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557\u2013572 (2004).","journal-title":"Biostatistics"},{"key":"BFsrep29267_CR33","doi-asserted-by":"publisher","first-page":"e46688","DOI":"10.1371\/journal.pone.0046688","volume":"7","author":"Y Choi","year":"2012","unstructured":"Choi, Y., Sims, G. E., Murphy, S., Miller, J. R. & Chan, A. P. Predicting the functional effect of amino acid substitutions and indels. PLoS One 7, e46688 (2012).","journal-title":"PLoS One"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep29267.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep29267","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep29267.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T06:31:26Z","timestamp":1672900286000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep29267"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,7]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,7,29]]}},"alternative-id":["BFsrep29267"],"URL":"https:\/\/doi.org\/10.1038\/srep29267","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,7]]},"assertion":[{"value":"17 February 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 July 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"29267"}}