Xiaohui Zhan1,2,3, Yusong Liu4,5, Christina Y Yu4,6, Tian-Fu Wang7, Jie Zhang8, Dong Ni9, Kun Huang10,11. 1. National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518037, China. xhzhan@cqmu.edu.cn. 2. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. xhzhan@cqmu.edu.cn. 3. School of Basic Medicine, Chongqing Medical University, Chongqing, 400016, China. xhzhan@cqmu.edu.cn. 4. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. 5. College of Automation, Harbin Engineering University, Harbin, 150001, Heilongjiang, China. 6. Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA. 7. National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518037, China. 8. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. 9. National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518037, China. nidong@szu.edu.cn. 10. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. kunhuang@iu.edu. 11. Regenstrief Institute, Indianapolis, 46202, USA. kunhuang@iu.edu.
Abstract
BACKGROUND: Renal cell carcinoma (RCC) is a complex disease and is comprised of several histological subtypes, the most frequent of which are clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (PRCC) and chromophobe renal cell carcinoma (ChRCC). While lots of studies have been performed to investigate the molecular characterizations of different subtypes of RCC, our knowledge regarding the underlying mechanisms are still incomplete. As molecular alterations are eventually reflected on the pathway level to execute certain biological functions, characterizing the pathway perturbations is crucial for understanding tumorigenesis and development of RCC. METHODS: In this study, we investigated the pathway perturbations of various RCC subtype against normal tissue based on differential expressed genes within a certain pathway. We explored the potential upstream regulators of subtype-specific pathways with Ingenuity Pathway Analysis (IPA). We also evaluated the relationships between subtype-specific pathways and clinical outcome with survival analysis. RESULTS: In this study, we carried out a pathway-based analysis to explore the mechanisms of various RCC subtypes with TCGA RNA-seq data. Both commonly altered pathways and subtype-specific pathways were detected. To identify the distinctive characteristics of each subtype, we focused on subtype-specific perturbed pathways. Specifically, we observed that some of the altered pathways were regulated by several recurrent upstream regulators which presenting different expression patterns among distinct RCC subtypes. We also noticed that a large number of perturbed pathways were controlled by the subtype-specific upstream regulators. Moreover, we also evaluated the relationships between perturbed pathways and clinical outcome. Prognostic pathways were identified and their roles in tumor development and progression were inferred. CONCLUSIONS: In summary, we evaluated the relationships among pathway perturbations, upstream regulators and clinical outcome for differential subtypes in RCC. We hypothesized that the alterations of common upstream regulators as well as subtype-specific upstream regulators work together to affect the downstream pathway perturbations and drive cancer initialization and prognosis. Our findings not only increase our understanding of the mechanisms of various RCC subtypes, but also provide targets for personalized therapeutic intervention.
BACKGROUND:Renal cell carcinoma (RCC) is a complex disease and is comprised of several histological subtypes, the most frequent of which are clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (PRCC) and chromophobe renal cell carcinoma (ChRCC). While lots of studies have been performed to investigate the molecular characterizations of different subtypes of RCC, our knowledge regarding the underlying mechanisms are still incomplete. As molecular alterations are eventually reflected on the pathway level to execute certain biological functions, characterizing the pathway perturbations is crucial for understanding tumorigenesis and development of RCC. METHODS: In this study, we investigated the pathway perturbations of various RCC subtype against normal tissue based on differential expressed genes within a certain pathway. We explored the potential upstream regulators of subtype-specific pathways with Ingenuity Pathway Analysis (IPA). We also evaluated the relationships between subtype-specific pathways and clinical outcome with survival analysis. RESULTS: In this study, we carried out a pathway-based analysis to explore the mechanisms of various RCC subtypes with TCGA RNA-seq data. Both commonly altered pathways and subtype-specific pathways were detected. To identify the distinctive characteristics of each subtype, we focused on subtype-specific perturbed pathways. Specifically, we observed that some of the altered pathways were regulated by several recurrent upstream regulators which presenting different expression patterns among distinct RCC subtypes. We also noticed that a large number of perturbed pathways were controlled by the subtype-specific upstream regulators. Moreover, we also evaluated the relationships between perturbed pathways and clinical outcome. Prognostic pathways were identified and their roles in tumor development and progression were inferred. CONCLUSIONS: In summary, we evaluated the relationships among pathway perturbations, upstream regulators and clinical outcome for differential subtypes in RCC. We hypothesized that the alterations of common upstream regulators as well as subtype-specific upstream regulators work together to affect the downstream pathway perturbations and drive cancer initialization and prognosis. Our findings not only increase our understanding of the mechanisms of various RCC subtypes, but also provide targets for personalized therapeutic intervention.
Authors: Christopher J Ricketts; Aguirre A De Cubas; Huihui Fan; Christof C Smith; Martin Lang; Ed Reznik; Reanne Bowlby; Ewan A Gibb; Rehan Akbani; Rameen Beroukhim; Donald P Bottaro; Toni K Choueiri; Richard A Gibbs; Andrew K Godwin; Scott Haake; A Ari Hakimi; Elizabeth P Henske; James J Hsieh; Thai H Ho; Rupa S Kanchi; Bhavani Krishnan; David J Kwiatkowski; Wembin Lui; Maria J Merino; Gordon B Mills; Jerome Myers; Michael L Nickerson; Victor E Reuter; Laura S Schmidt; C Simon Shelley; Hui Shen; Brian Shuch; Sabina Signoretti; Ramaprasad Srinivasan; Pheroze Tamboli; George Thomas; Benjamin G Vincent; Cathy D Vocke; David A Wheeler; Lixing Yang; William Y Kim; A Gordon Robertson; Paul T Spellman; W Kimryn Rathmell; W Marston Linehan Journal: Cell Rep Date: 2018-06-19 Impact factor: 9.423
Authors: W Marston Linehan; Gennady Bratslavsky; Peter A Pinto; Laura S Schmidt; Len Neckers; Donald P Bottaro; Ramaprasad Srinivasan Journal: Annu Rev Med Date: 2010 Impact factor: 13.739