| Autor: |
Suneetha Chintalapati, Jeffrey A. Cadeddu, Satwik Rajaram, Payal Kapur, Dinesh Rakheja, Vitaly Margulis, Qinbo Zhou, Alana Christie, Renee M. McKay, Qi Cai, James Brugarolas, Nirmish Singla, Ellen Araj, Min Kim, Ivan Pedrosa |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
SSRN Electronic Journal. |
| ISSN: |
1556-5068 |
| Popis: |
Clear cell renal cell carcinoma (ccRCC) exemplifies intratumoral heterogeneity that provides a framework to study tumor evolution. Multiregional genomic sample analyses have shown that tumors evolve from an ancient clone that over time acquires metastatic competency. However, these analyses have been conducted agnostic of the phenotype. Here, we established a systematic ontology of ccRCC phenotypic variability by developing a multi-scale framework along three fundamental axes: tumor architecture, cytology and microenvironment. We comprehensively evaluated 33 parameters retrospectively in 549 consecutive ccRCCs. We discovered novel ccRCC subtypes and an integrated taxonomy that has prognostic implications beyond current parameters used for prognosis. Specifically, we found a subset of ccRCC morphologies associated with aggressive biology and significantly worse outcomes. Dimensionality reduction by t-distributed stochastic neighbor embedding revealed distinct ccRCC subtypes with converging evolutionary trajectories into an aggressive class. Furthermore, we found that there was preferential selection for the more advanced phenotypes in the tumor thrombus and in tumors with stable engraftment in patient derived xenograft model. These data provide critical insight into the phenotypic evolution of ccRCC, that can inform patient selection for clinical care. We believe that this work sets a paradigm for deconvoluting tumor complexity that is applicable to other cancer types. Funding: This work was supported by Cancer Prevention and Research Institute of Texas grant RP130603 (J. Brugarolas) and P50CA196516 (A. Christie, I. Pedrosa, D. Rakheja, R. McKay, J. Brugarolas and P. Kapur). Declaration of Interest: None. Ethical Approval: The study was approved by the UT Southwestern Medical Center (UTSW) Institutional Review Board (IRB) and conducted according to the Health Insurance Portability and Accountability Act (HIPAA) guidelines. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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