Oral Presentation HUPO 2019 - 18th Human Proteome Organization World Congress

Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma (#173)

David J Clark 1 , Saravana M Dhanasekaran 2 , Francesca Petralia 3 , Jianbo Pan 1 , Xiaoyu Song 4 , Yingwei Hu 1 , Felipe da Veiga Leprevost 2 , Boris Reva 3 , Tung-Shing M Lih 1 , Hui-Yin Chang 2 , Weiping Ma 3 , Chen Huang 5 , Christopher J Ricketts 6 , Lijun Chen 1 , Azra Krek 3 , Yize Li 7 , Dmitry Rykunov 3 , Qing Kay Li 1 , Lin S Chen 8 , Umut Ozbek 4 , Suhas Vasaikar 9 , Shrabanti Chowdhury 3 , Yige Wu 7 , Seungyeul Yoo 3 , Shrabanti Chowdhury 3 , Matthew A Wyczalkowski 7 , Jiayi Ji 3 , Michael Schnaubelt 1 , Andy Kong 2 , Sunantha Sethuraman 7 , Dmitry M Avtonomov 2 , Minghui Ao 1 , Antonio Colaprico 10 , Song Cao 7 , Kyung-Cho Cho 1 , Selim Kalayci 3 , Shiyong Ma 1 , Wenke Liu 11 , Anna Calinawan 3 , Zeynep H Gumus 3 , Feng Chen 12 , Nathan Edwards 13 , Phillip M Pieroazio 14 , Xi Steven Chen 15 , Christian P Pavlovich 14 , A. Ari Hakimi 16 , Gabriel Brominski 17 , James J Hsieh 18 , Andrzej Antczak 17 , Tatiana Omelchenko 19 , Jan Lubinski 20 , Maciej Wiznerowicz 17 , W. Marston Linehan 6 , Chris R Kinsinger 21 , Mathangi Thiagarajan 22 , Emily S Boja 21 , Mehdi Mesri 21 , Tara Hiltke 21 , Ana I Robles 21 , Henry Rodriguez 21 , Jiang Qian 23 , David Fenyo 11 , Bing Zhang 24 , Li Ding 7 , Eric Schadt 3 , Arul Chinnaiyan 2 , Zhen Zhang 1 , Gil Omenn 25 , Marcin Cieslik 2 , Daniel Chan 1 , Alexey I Nesvizhskii 2 , Pei Wang 3 , Hui Zhang 1
  1. Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA
  2. Department of Pathology, University of Michigan, Ann Arbor, MI, USA
  3. Department of Genetics & Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, New York, NY, USA
  4. Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  5. Lester and Sue Smith Breast Cancer Center, Baylor College of Medicine, Houston, TX, USA
  6. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
  7. Washington University School of Medicine, St. Louis, MO, USA
  8. Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
  9. Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA
  10. Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
  11. Institute for Systems Genetics and Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, USA
  12. Departments of Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
  13. Department of Biochemistry & Cellular Biology, Georgetown University, Washington D.C., USA
  14. Brady Urological Institute and Department of Urology, The Johns Hopkins University, Baltimore, MD, USA
  15. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
  16. Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  17. Poznan University of Medical Sciences, Poznan, Poland
  18. Department of Medicine, , Washington University School of Medicine, St. Louis, MO, USA
  19. Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  20. Pomeranian University of Medicine, Szczecin, Poland
  21. Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, USA
  22. Frederick National Laboratory for Cancer Research, Frederick, MD, USA
  23. Department of Ophthalmology, The Johns Hopkins University, Baltimore, MD, USA
  24. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  25. Departments of Computational Medicine & Bioinformatics, Internal Medicine, Human Genetics, and School of Public Health, University of Michigan, Ann Arbor, MI, USA

Background: Clear cell renal cell carcinoma (ccRCC) is the most predominant histology of renal cancer, representing 75% of all cases and accounting for the majority of associated deaths. To gain insight into the impact of genomic alterations on the functional modules that drive ccRCC tumorigenesis, we leveraged comprehensive proteogenomic characterization of 110 treatment-naïve renal cell carcinoma (RCC) and 84 paired-matched normal adjacent tissue (NAT) samples.

 

Methods: We utilized an integrated proteogenomic approach, performing whole genome sequencing (WGS), whole exome sequencing (WES), DNA methylation profiling for all tumors; RNA-seq, proteomic, and phosphoproteomic characterization was performed for all samples.

 

Results: WGS analysis revealed arm-level loss of chromosome 3p as a frequent event in ccRCC, with 61% of tumors showing evidence of 3p chromosomal translocation events. Comparative profiling of ccRCC and NATs samples identified pathways associated with immune response, EMT, and glycolysis to be up-regulated in ccRCC, while TCA cycle, fatty acid metabolism, and oxidative phosphorylation were down-regulated. Examination of mRNA-protein correlation revealed a non-linear relationship in cellular processes including Warburg Effect-related metabolism, as well as the tumor-specific trend of higher sample-wise correlation associating with prognostically-defined aggressive features of ccRCC. Analysis of differential phosphosite occupancy between tumors and NAT showed MAPK/ERK signalling and G2/M stalling to be up-regulated across the majority of ccRCC cases. We deconvoluted immune and stromal cell gene signatures in the tumor microenvironment (TME), with consensus clustering of the TME compositions identifying four immune-based subtypes: Inflamed CD8+, Inflamed CD8-, VEGF Immune Desert, and Metabolic Immune Desert. Integrated transcriptomic and proteomic profiling of the ccRCC subtypes revealed unique, discriminatory signalling pathways associated with immune exhaustion, cancer-associated fibroblast-related signalling, angiogenesis, and metabolic activity.

 

Conclusions: Our results link the functional impact of genomic alterations at the protein level, and provides evidence for rational treatment selection stemming from proteomic, phosphoproteomic, and tumor microenvironment signatures.