Proteogenomic characterization of pancreatic ductal adenocarcinoma

Liwei Cao; Chen Huang; Daniel Cui Zhou; Yingwei Hu; T Mamie Lih; Sara R Savage; Karsten Krug; David J Clark; Michael Schnaubelt; Lijun Chen; Felipe da Veiga Leprevost; Rodrigo Vargas Eguez; Weiming Yang; Jianbo Pan; Bo Wen; Yongchao Dou; Wen Jiang; Yuxing Liao; Zhiao Shi; Nadezhda V Terekhanova; Song Cao; Rita Jui-Hsien Lu; Yize Li; Ruiyang Liu; Houxiang Zhu; Peter Ronning; Yige Wu; Matthew A Wyczalkowski; Hariharan Easwaran; Ludmila Danilova; Arvind Singh Mer; Seungyeul Yoo; Joshua M Wang; Wenke Liu; Benjamin Haibe-Kains; Mathangi Thiagarajan; Scott D Jewell; Galen Hostetter; Chelsea J Newton; Qing Kay Li; Michael H Roehrl; David Fenyö; Pei Wang; Alexey I Nesvizhskii; D R Mani; Gilbert S Omenn; Emily S Boja; Mehdi Mesri; Ana I Robles; Henry Rodriguez; Oliver F Bathe; Daniel W Chan; Ralph H Hruban; Li Ding; Bing Zhang; Hui Zhang; Clinical Proteomic Tumor Analysis Consortium

doi:10.1016/j.cell.2021.08.023

Proteogenomic characterization of pancreatic ductal adenocarcinoma

Cell. 2021 Sep 16;184(19):5031-5052.e26. doi: 10.1016/j.cell.2021.08.023.

Authors

Liwei Cao¹, Chen Huang², Daniel Cui Zhou³, Yingwei Hu¹, T Mamie Lih¹, Sara R Savage², Karsten Krug⁴, David J Clark¹, Michael Schnaubelt¹, Lijun Chen¹, Felipe da Veiga Leprevost⁵, Rodrigo Vargas Eguez¹, Weiming Yang¹, Jianbo Pan¹, Bo Wen², Yongchao Dou², Wen Jiang², Yuxing Liao², Zhiao Shi², Nadezhda V Terekhanova³, Song Cao³, Rita Jui-Hsien Lu³, Yize Li³, Ruiyang Liu³, Houxiang Zhu³, Peter Ronning³, Yige Wu³, Matthew A Wyczalkowski³, Hariharan Easwaran⁶, Ludmila Danilova⁷, Arvind Singh Mer⁸, Seungyeul Yoo⁹, Joshua M Wang¹⁰, Wenke Liu¹⁰, Benjamin Haibe-Kains¹¹, Mathangi Thiagarajan¹², Scott D Jewell¹³, Galen Hostetter¹³, Chelsea J Newton¹³, Qing Kay Li¹, Michael H Roehrl¹⁴, David Fenyö¹⁰, Pei Wang⁹, Alexey I Nesvizhskii⁵, D R Mani⁴, Gilbert S Omenn¹⁵, Emily S Boja¹⁶, Mehdi Mesri¹⁶, Ana I Robles¹⁶, Henry Rodriguez¹⁶, Oliver F Bathe¹⁷, Daniel W Chan¹⁸, Ralph H Hruban¹⁹, Li Ding²⁰, Bing Zhang²¹, Hui Zhang²²; Clinical Proteomic Tumor Analysis Consortium

Collaborators

Clinical Proteomic Tumor Analysis Consortium:
Mitual Amin, Eunkyung An, Christina Ayad, Thomas Bauer, Chet Birger, Michael J Birrer, Simina M Boca, William Bocik, Melissa Borucki, Shuang Cai, Steven A Carr, Sandra Cerda, Huan Chen, Steven Chen, David Chesla, Arul M Chinnaiyan, Antonio Colaprico, Sandra Cottingham, Magdalena Derejska, Saravana M Dhanasekaran, Marcin J Domagalski, Brian J Druker, Elizabeth Duffy, Maureen A Dyer, Nathan J Edwards, Matthew J Ellis, Jennifer Eschbacher, Alicia Francis, Jesse Francis, Stacey Gabriel, Nikolay Gabrovski, Johanna Gardner, Gad Getz, Michael A Gillette, Charles A Goldthwaite Jr, Pamela Grady, Shuai Guo, Pushpa Hariharan, Tara Hiltke, Barbara Hindenach, Katherine A Hoadley, Jasmine Huang, Corbin D Jones, Karen A Ketchum, Christopher R Kinsinger, Jennifer M Koziak, Katarzyna Kusnierz, Tao Liu, Jiang Long, David Mallery, Sailaja Mareedu, Ronald Matteotti, Nicollette Maunganidze, Peter B McGarvey, Parham Minoo, Oxana V Paklina, Amanda G Paulovich, Samuel H Payne, Olga Potapova, Barbara Pruetz, Liqun Qi, Nancy Roche, Karin D Rodland, Daniel C Rohrer, Eric E Schadt, Alexey V Shabunin, Troy Shelton, Yvonne Shutack, Shilpi Singh, Michael Smith, Richard D Smith, Lori J Sokoll, James Suh, Ratna R Thangudu, Shirley X Tsang, Ki Sung Um, Dana R Valley, Negin Vatanian, Wenyi Wang, George D Wilson, Maciej Wiznerowicz, Zhen Zhang, Grace Zhao

Affiliations

¹ Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA.
² Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.
⁴ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
⁵ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
⁷ Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
⁹ Sema4, a Mount Sinai venture, Stamford, CT 06902, USA.
¹⁰ Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.
¹¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
¹² Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
¹³ Van Andel Research Institute, Grand Rapids, MI 49503, USA.
¹⁴ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁵ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁶ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA.
¹⁷ Departments of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁸ Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
¹⁹ Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21231, USA.
²⁰ Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA. Electronic address: lding@wustl.edu.
²¹ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bing.zhang@bcm.edu.
²² Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: huizhang@jhu.edu.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.

Keywords: CPTAC; KRAS; endothelial cell; glycoproteins; immune-cold tumors; kinase inhibitors; neoplastic cellularity; pancreatic ductal adenocarcinoma; proteogenomics; tumor subtyping.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / diagnosis
Adenocarcinoma / genetics*
Adult
Aged
Aged, 80 and over
Algorithms
Carcinoma, Pancreatic Ductal / diagnosis
Carcinoma, Pancreatic Ductal / genetics*
Cohort Studies
Endothelial Cells / metabolism
Epigenesis, Genetic
Female
Gene Dosage
Genome, Human
Glycolysis
Glycoproteins / biosynthesis
Humans
Male
Middle Aged
Molecular Targeted Therapy
Pancreatic Neoplasms / diagnosis
Pancreatic Neoplasms / genetics*
Phenotype
Phosphoproteins / metabolism
Phosphorylation
Prognosis
Protein Kinases / metabolism
Proteogenomics*
Proteome / metabolism
Substrate Specificity
Transcriptome / genetics

Substances

Glycoproteins
Phosphoproteins
Proteome
Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding