Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive typeResearch in context
Background: Clear cell renal cell carcinoma (ccRCC) is a particularly challenging tumor type because of its extensive phenotypic variability as well as intra-tumoral heterogeneity (ITH). Clinically, this complexity has been reduced to a handful of pathological variables such as stage, grade and necr...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419307273 |
| _version_ | 1818951722189455360 |
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| author | Qi Cai Alana Christie Satwik Rajaram Qinbo Zhou Ellen Araj Suneetha Chintalapati Jeffrey Cadeddu Vitaly Margulis Ivan Pedrosa Dinesh Rakheja Renee M. McKay James Brugarolas Payal Kapur |
| author_facet | Qi Cai Alana Christie Satwik Rajaram Qinbo Zhou Ellen Araj Suneetha Chintalapati Jeffrey Cadeddu Vitaly Margulis Ivan Pedrosa Dinesh Rakheja Renee M. McKay James Brugarolas Payal Kapur |
| author_sort | Qi Cai |
| collection | DOAJ |
| description | Background: Clear cell renal cell carcinoma (ccRCC) is a particularly challenging tumor type because of its extensive phenotypic variability as well as intra-tumoral heterogeneity (ITH). Clinically, this complexity has been reduced to a handful of pathological variables such as stage, grade and necrosis, but these variables fail to capture the breadth of the disease. How different phenotypes affect patient prognosis and influence therapeutic response is poorly understood. Extensive ITH illustrates remarkable plasticity, providing a framework to study tumor evolution. While multiregional genomic analyses have shown evolution from an ancient clone that acquires metastatic competency over time, these studies have been conducted agnostic to morphological cues and phenotypic plasticity. Methods: We established a systematic ontology of ccRCC phenotypic variability by developing a multi-scale framework along three fundamental axes: tumor architecture, cytology and the microenvironment. We defined 33 parameters, which we comprehensively evaluated in 549 consecutive ccRCCs retrospectively. We systematically evaluated the impact of each parameter on patient outcomes, and assessed their contribution through multivariate analyses. We measured therapeutic impact in the context of anti-angiogenic therapies. We applied dimensionality reduction by t-distributed stochastic neighbor embedding (t-SNE) algorithms to tumor architectures for the study of tumor evolution superimposing tumor size and grade vectors. Evolutionary models were refined through empirical analyses of directed evolution of tumor intravascular extensions, and metastatic competency (as determined by tumor reconstitution in a heterologous host). Findings: We discovered several novel ccRCC phenotypes, developed an integrated taxonomy, and identified features that improve current prognostic models. We identified a subset of ccRCCs refractory to anti-angiogenic therapies. We developed a model of tumor evolution, which revealed converging evolutionary trajectories into an aggressive type. Interpretation: This work serves as a paradigm for deconvoluting tumor complexity and illustrates how morphological analyses can improve our understanding of ccRCC pleiotropy. We identified several subtypes associated with aggressive biology, and differential response to targeted therapies. By analyzing patterns of spatial and temporal co-occurrence, intravascular tumor extensions and metastatic competency, we were able to identify distinct trajectories of convergent phenotypic evolution. Keywords: ccRCC, Morphologic heterogeneity, Prognosis, Tumor evolution, Angiogenesis inhibitors, TKIs, Immune checkpoint inhibitors |
| first_indexed | 2024-12-20T09:39:00Z |
| format | Article |
| id | doaj.art-2150c4952b1d46199115476db424b46b |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-20T09:39:00Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-2150c4952b1d46199115476db424b46b2022-12-21T19:44:56ZengElsevierEBioMedicine2352-39642020-01-0151Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive typeResearch in contextQi Cai0Alana Christie1Satwik Rajaram2Qinbo Zhou3Ellen Araj4Suneetha Chintalapati5Jeffrey Cadeddu6Vitaly Margulis7Ivan Pedrosa8Dinesh Rakheja9Renee M. McKay10James Brugarolas11Payal Kapur12Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesKidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesDepartment of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesDepartment of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Institute for Urology and Reproductive Health, Sechenov University, Moscow, RussiaDepartment of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesKidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United StatesDepartment of Internal Medicine, Hematology-Oncology Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Corresponding authors at: Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Corresponding authors at: Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.Background: Clear cell renal cell carcinoma (ccRCC) is a particularly challenging tumor type because of its extensive phenotypic variability as well as intra-tumoral heterogeneity (ITH). Clinically, this complexity has been reduced to a handful of pathological variables such as stage, grade and necrosis, but these variables fail to capture the breadth of the disease. How different phenotypes affect patient prognosis and influence therapeutic response is poorly understood. Extensive ITH illustrates remarkable plasticity, providing a framework to study tumor evolution. While multiregional genomic analyses have shown evolution from an ancient clone that acquires metastatic competency over time, these studies have been conducted agnostic to morphological cues and phenotypic plasticity. Methods: We established a systematic ontology of ccRCC phenotypic variability by developing a multi-scale framework along three fundamental axes: tumor architecture, cytology and the microenvironment. We defined 33 parameters, which we comprehensively evaluated in 549 consecutive ccRCCs retrospectively. We systematically evaluated the impact of each parameter on patient outcomes, and assessed their contribution through multivariate analyses. We measured therapeutic impact in the context of anti-angiogenic therapies. We applied dimensionality reduction by t-distributed stochastic neighbor embedding (t-SNE) algorithms to tumor architectures for the study of tumor evolution superimposing tumor size and grade vectors. Evolutionary models were refined through empirical analyses of directed evolution of tumor intravascular extensions, and metastatic competency (as determined by tumor reconstitution in a heterologous host). Findings: We discovered several novel ccRCC phenotypes, developed an integrated taxonomy, and identified features that improve current prognostic models. We identified a subset of ccRCCs refractory to anti-angiogenic therapies. We developed a model of tumor evolution, which revealed converging evolutionary trajectories into an aggressive type. Interpretation: This work serves as a paradigm for deconvoluting tumor complexity and illustrates how morphological analyses can improve our understanding of ccRCC pleiotropy. We identified several subtypes associated with aggressive biology, and differential response to targeted therapies. By analyzing patterns of spatial and temporal co-occurrence, intravascular tumor extensions and metastatic competency, we were able to identify distinct trajectories of convergent phenotypic evolution. Keywords: ccRCC, Morphologic heterogeneity, Prognosis, Tumor evolution, Angiogenesis inhibitors, TKIs, Immune checkpoint inhibitorshttp://www.sciencedirect.com/science/article/pii/S2352396419307273 |
| spellingShingle | Qi Cai Alana Christie Satwik Rajaram Qinbo Zhou Ellen Araj Suneetha Chintalapati Jeffrey Cadeddu Vitaly Margulis Ivan Pedrosa Dinesh Rakheja Renee M. McKay James Brugarolas Payal Kapur Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive typeResearch in context EBioMedicine |
| title | Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive typeResearch in context |
| title_full | Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive typeResearch in context |
| title_fullStr | Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive typeResearch in context |
| title_full_unstemmed | Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive typeResearch in context |
| title_short | Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive typeResearch in context |
| title_sort | ontological analyses reveal clinically significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive typeresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419307273 |
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