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1. The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution

Author

Orit Rozenblatt-Rosen, Aviv Regev, Philipp Oberdoerffer, Tal Nawy, Anna Hupalowska, Jennifer E. Rood, Orr Ashenberg, Ethan Cerami, Robert J. Coffey, Emek Demir, Li Ding, Edward D. Esplin, James M. Ford, Jeremy Goecks, Sharmistha Ghosh, Joe W. Gray, Justin Guinney, Sean E. Hanlon, Shannon K. Hughes, E. Shelley Hwang, Christine A. Iacobuzio-Donahue, Judit Jané-Valbuena, Bruce E. Johnson, Ken S. Lau, Tracy Lively, Sarah A. Mazzilli, Dana Pe’er, Sandro Santagata, Alex K. Shalek, Denis Schapiro, Michael P. Snyder, Peter K. Sorger, Avrum E. Spira, Sudhir Srivastava, Kai Tan, Robert B. West, Elizabeth H. Williams, Denise Aberle, Samuel I. Achilefu, Foluso O. Ademuyiwa, Andrew C. Adey, Rebecca L. Aft, Rachana Agarwal, Ruben A. Aguilar, Fatemeh Alikarami, Viola Allaj, Christopher Amos, Robert A. Anders, Michael R. Angelo, Kristen Anton, Jon C. Aster, Ozgun Babur, Amir Bahmani, Akshay Balsubramani, David Barrett, Jennifer Beane, Diane E. Bender, Kathrin Bernt, Lynne Berry, Courtney B. Betts, Julie Bletz, Katie Blise, Adrienne Boire, Genevieve Boland, Alexander Borowsky, Kristopher Bosse, Matthew Bott, Ed Boyden, James Brooks, Raphael Bueno, Erik A. Burlingame, Qiuyin Cai, Joshua Campbell, Wagma Caravan, Hassan Chaib, Joseph M. Chan, Young Hwan Chang, Deyali Chatterjee, Ojasvi Chaudhary, Alyce A. Chen, Bob Chen, Changya Chen, Chia-hui Chen, Feng Chen, Yu-An Chen, Milan G. Chheda, Koei Chin, Roxanne Chiu, Shih-Kai Chu, Rodrigo Chuaqui, Jaeyoung Chun, Luis Cisneros, Graham A. Colditz, Kristina Cole, Natalie Collins, Kevin Contrepois, Lisa M. Coussens, Allison L. Creason, Daniel Crichton, Christina Curtis, Tanja Davidsen, Sherri R. Davies, Ino de Bruijn, Laura Dellostritto, Angelo De Marzo, David G. DeNardo, Dinh Diep, Sharon Diskin, Xengie Doan, Julia Drewes, Stephen Dubinett, Michael Dyer, Jacklynn Egger, Jennifer Eng, Barbara Engelhardt, Graham Erwin, Laura Esserman, Alex Felmeister, Heidi S. Feiler, Ryan C. Fields, Stephen Fisher, Keith Flaherty, Jennifer Flournoy, Angelo Fortunato, Allison Frangieh, Jennifer L. Frye, Robert S. Fulton, Danielle Galipeau, Siting Gan, Jianjiong Gao, Long Gao, Peng Gao, Vianne R. Gao, Tim Geiger, Ajit George, Gad Getz, Marios Giannakis, David L. Gibbs, William E. Gillanders, Simon P. Goedegebuure, Alanna Gould, Kate Gowers, William Greenleaf, Jeremy Gresham, Jennifer L. Guerriero, Tuhin K. Guha, Alexander R. Guimaraes, David Gutman, Nir Hacohen, Sean Hanlon, Casey R. Hansen, Olivier Harismendy, Kathleen A. Harris, Aaron Hata, Akimasa Hayashi, Cody Heiser, Karla Helvie, John M. Herndon, Gilliam Hirst, Frank Hodi, Travis Hollmann, Aaron Horning, James J. Hsieh, Shannon Hughes, Won Jae Huh, Stephen Hunger, Shelley E. Hwang, Heba Ijaz, Benjamin Izar, Connor A. Jacobson, Samuel Janes, Reyka G. Jayasinghe, Lihua Jiang, Brett E. Johnson, Bruce Johnson, Tao Ju, Humam Kadara, Klaus Kaestner, Jacob Kagan, Lukas Kalinke, Robert Keith, Aziz Khan, Warren Kibbe, Albert H. Kim, Erika Kim, Junhyong Kim, Annette Kolodzie, Mateusz Kopytra, Eran Kotler, Robert Krueger, Kostyantyn Krysan, Anshul Kundaje, Uri Ladabaum, Blue B. Lake, Huy Lam, Rozelle Laquindanum, Ashley M. Laughney, Hayan Lee, Marc Lenburg, Carina Leonard, Ignaty Leshchiner, Rochelle Levy, Jerry Li, Christine G. Lian, Kian-Huat Lim, Jia-Ren Lin, Yiyun Lin, Qi Liu, Ruiyang Liu, William J.R. Longabaugh, Teri Longacre, Cynthia X. Ma, Mary Catherine Macedonia, Tyler Madison, Christopher A. Maher, Anirban Maitra, Netta Makinen, Danika Makowski, Carlo Maley, Zoltan Maliga, Diego Mallo, John Maris, Nick Markham, Jeffrey Marks, Daniel Martinez, Robert J. Mashl, Ignas Masilionais, Jennifer Mason, Joan Massagué, Pierre Massion, Marissa Mattar, Richard Mazurchuk, Linas Mazutis, Eliot T. McKinley, Joshua F. McMichael, Daniel Merrick, Matthew Meyerson, Julia R. Miessner, Gordon B. Mills, Meredith Mills, Suman B. Mondal, Motomi Mori, Yuriko Mori, Elizabeth Moses, Yael Mosse, Jeremy L. Muhlich, George F. Murphy, Nicholas E. Navin, Michel Nederlof, Reid Ness, Stephanie Nevins, Milen Nikolov, Ajit Johnson Nirmal, Garry Nolan, Edward Novikov, Brendan O’Connell, Michael Offin, Stephen T. Oh, Anastasiya Olson, Alex Ooms, Miguel Ossandon, Kouros Owzar, Swapnil Parmar, Tasleema Patel, Gary J. Patti, Itsik Pe'er, Tao Peng, Daniel Persson, Marvin Petty, Hanspeter Pfister, Kornelia Polyak, Kamyar Pourfarhangi, Sidharth V. Puram, Qi Qiu, Álvaro Quintanal-Villalonga, Arjun Raj, Marisol Ramirez-Solano, Rumana Rashid, Ashley N. Reeb, Mary Reid, Adam Resnick, Sheila M. Reynolds, Jessica L. Riesterer, Scott Rodig, Joseph T. Roland, Sonia Rosenfield, Asaf Rotem, Sudipta Roy, Charles M. Rudin, Marc D. Ryser, Maria Santi-Vicini, Kazuhito Sato, Deborah Schrag, Nikolaus Schultz, Cynthia L. Sears, Rosalie C. Sears, Subrata Sen, Triparna Sen, Alex Shalek, Jeff Sheng, Quanhu Sheng, Kooresh I. Shoghi, Martha J. Shrubsole, Yu Shyr, Alexander B. Sibley, Kiara Siex, Alan J. Simmons, Dinah S. Singer, Shamilene Sivagnanam, Michal Slyper, Artem Sokolov, Sheng-Kwei Song, Austin Southard-Smith, Avrum Spira, Janet Stein, Phillip Storm, Elizabeth Stover, Siri H. Strand, Timothy Su, Damir Sudar, Ryan Sullivan, Lea Surrey, Mario Suvà, Nadezhda V. Terekhanova, Luke Ternes, Lisa Thammavong, Guillaume Thibault, George V. Thomas, Vésteinn Thorsson, Ellen Todres, Linh Tran, Madison Tyler, Yasin Uzun, Anil Vachani, Eliezer Van Allen, Simon Vandekar, Deborah J. Veis, Sébastien Vigneau, Arastoo Vossough, Angela Waanders, Nikhil Wagle, Liang-Bo Wang, Michael C. Wendl, Robert West, Chi-yun Wu, Hao Wu, Hung-Yi Wu, Matthew A. Wyczalkowski, Yubin Xie, Xiaolu Yang, Clarence Yapp, Wenbao Yu, Yinyin Yuan, Dadong Zhang, Kun Zhang, Mianlei Zhang, Nancy Zhang, Yantian Zhang, Yanyan Zhao, Daniel Cui Zhou, Zilu Zhou, Houxiang Zhu, Qin Zhu, Xiangzhu Zhu, Yuankun Zhu, and Xiaowei Zhuang

Subjects
Cell, Genomics, Computational biology, Tumor initiation, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Metastasis, 03 medical and health sciences, Atlases as Topic, 0302 clinical medicine, Neoplasms, Tumor Microenvironment, medicine, Humans, Precision Medicine, 030304 developmental biology, 0303 health sciences, Atlas (topology), Cancer, medicine.disease, 3. Good health, Human tumor, Cell Transformation, Neoplastic, medicine.anatomical_structure, Single-Cell Analysis, Single point, 030217 neurology & neurosurgery
Abstract

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

Published
2020
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2. Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

Author

Matthew E. Monroe, Saravana M. Dhanasekaran, Brian R. Rood, Zeynep H. Gümüş, Jena Lilly, Samuel G. Winebrake, Richard G. Ivey, William Bocik, Mahdi Sarmady, Alicia Francis, Lamiya Tauhid, Nathan Edwards, Lizabeth Katsnelson, Rui Zhao, Matilda Broberg, Jo Lynne Rokita, Mateusz Koptyra, Henry Rodriguez, Cassie Kline, Shrabanti Chowdhury, Nicole Tignor, Ying Wang, Christopher R. Kinsinger, Antonio Colaprico, Amanda G. Paulovich, Weiping Ma, Emily S. Boja, Tara Hiltke, Sabine Mueller, Liang-Bo Wang, Javad Nazarian, Marcin J. Domagalski, Karl K. Weitz, Jessica B. Foster, Robert Lober, Carina A. Leonard, Bo Zhang, Gerald A. Grant, Anna Calinawan, Gonzalo Lopez, Shuang Cai, Joanna J. Phillips, Guo Ci Teo, July E. Palma, Felipe da Veiga Leprevost, Yiran Guo, Angela Waanders, Xiaoyu Song, Li Ding, Allison Heath, Steven P. Gygi, Rosalie K. Chu, Vasileios Stathias, Bailey Farrow, Oren J. Becher, Dmitry Rykunov, Nithin D. Adappa, Ron Firestein, Adam C. Resnick, Marcin Cieślik, Jennifer Mason, D. R. Mani, Selim Kalayci, Boris Reva, Antonio Iavarone, MacIntosh Cornwell, Uliana J. Voytovich, Gabrielle S. Stone, Miguel A. Brown, Jacob J. Kennedy, Tao Liu, Ronald J. Moore, Emily Kawaler, Eric H. Raabe, Marina A. Gritsenko, Valerie Baubet, Francesca Petralia, Maciej Wiznerowicz, Olena Morozova Vaske, Eric E. Schadt, Ian F. Pollack, Arul M. Chinnaiyan, Meghan Connors, Jason E. Cain, Lei Zhao, Matthew A. Wyczalkowski, Nalin Gupta, Bing Zhang, Jiayi Ji, Marilyn M. Li, Samuel Rivero-Hinojosa, Mariarita Santi, Wenke Liu, John Szpyt, Brian Ennis, Alexey I. Nesvizhskii, Joshua M. Wang, Jeffrey P. Greenfield, Sanjukta Guha Thakurta, Hui Yin Chang, Peter B. McGarvey, Xi Chen, Karen A. Ketchum, Stephan C. Schürer, Sarah Leary, Lili Blumenberg, Matthew J. Ellis, Pei Wang, Anna Maria Buccoliero, Karsten Krug, Chiara Caporalini, Gad Getz, David E. Kram, Pichai Raman, Eric M. Jackson, James N. Palmer, Mehdi Mesri, Kelly V. Ruggles, Chunde Li, Jun Zhu, Sonia Partap, Jeffrey R. Whiteaker, Mirko Scagnet, Krutika S. Gaonkar, Azra Krek, Allison M. Morgan, Tatiana Omelchenko, Richard D. Smith, Elizabeth Appert, Karin D. Rodland, Derek Hanson, Phillip B. Storm, Jamie Moon, Vladislav A. Petyuk, Nathan Young, Travis D. Lorentzen, David Fenyö, Angela N. Viaene, Seungyeul Yoo, Yuankun Zhu, Nicholas A Vitanza, Toan Le, Tatiana Patton, and Ana I. Robles

Subjects
DNA Copy Number Variations, Computational biology, Biology, Proteomics, Article, General Biochemistry, Genetics and Molecular Biology, Ganglioglioma, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Glioma, medicine, Humans, Gene Regulatory Networks, RNA, Messenger, Copy-number variation, Phosphorylation, Child, Proteogenomics, 030304 developmental biology, Medulloblastoma, 0303 health sciences, Brain Neoplasms, Genome, Human, Phosphoproteomics, Phosphoproteins, medicine.disease, Gene Expression Regulation, Neoplastic, Mutation, Atypical teratoid rhabdoid tumor, Neoplasm Grading, Neoplasm Recurrence, Local, Transcriptome, 030217 neurology & neurosurgery
Abstract

We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.

Published
2020
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3. Proteogenomic Characterization of Ovarian HGSC Implicates Mitotic Kinases, Replication Stress in Observed Chromosomal Instability

Author

Zhen Zhang, Tao Liu, Karin D. Rodland, Christopher R. Kinsinger, Ehwang Song, Molly Brewer, Osama A. Arshad, Steven M. Foltz, Emily S. Boja, Chen Huang, Liang-Bo Wang, Mathangi Thiagarajan, Ronald J. Moore, Marina A. Gritsenko, Michael Schnaubelt, Vladislav A. Petyuk, Samuel H. Payne, Yige Wu, Rui Zhao, Therese R. W. Clauss, Jason E. McDermott, Matthew E. Monroe, Athena A. Schepmoes, Henry Rodriguez, Richard D. Smith, Chia-Feng Tsai, Daniel W. Chan, Bing Zhang, Yi Fu, Matthew A. Wyczalkowski, Li Ding, and Ana I. Robles

Subjects
Adult, DNA Replication, Mitosis, Context (language use), Biology, medicine.disease_cause, Proteomics, Article, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, proteomics, Chromosomal Instability, Chromosome instability, medicine, Fallopian Tube Neoplasms, Humans, Aged, Aged, 80 and over, Ovarian Neoplasms, Mutation, fallopian tube, lcsh:R5-920, Phosphotransferases, Phosphoproteomics, Cancer, phosphoproteomics, Cell Cycle Checkpoints, Middle Aged, medicine.disease, Cystadenocarcinoma, Serous, Gene Expression Regulation, Neoplastic, homologous repair deficiency, Histone, ovarian cancer, proteogenomics, Cancer research, biology.protein, Female, Tumor Suppressor Protein p53, Transcriptome, Ovarian cancer, lcsh:Medicine (General), DNA Damage
Abstract

SUMMARY In the absence of a dominant driving mutation other than uniformly present TP53 mutations, deeper understanding of the biology driving ovarian high-grade serous cancer (HGSC) requires analysis at a functional level, including post-translational modifications. Comprehensive proteogenomic and phosphoproteomic characterization of 83 prospectively collected ovarian HGSC and appropriate normal precursor tissue samples (fallopian tube) under strict control of ischemia time reveals pathways that significantly differentiate between HGSC and relevant normal tissues in the context of homologous repair deficiency (HRD) status. In addition to confirming key features of HGSC from previous studies, including a potential survival-associated signature and histone acetylation as a marker of HRD, deep phosphoproteomics provides insights regarding the potential role of proliferation-induced replication stress in promoting the characteristic chromosomal instability of HGSC and suggests potential therapeutic targets for use in precision medicine trials., Graphical Abstract, In Brief McDermott et al. present the proteogenomic analysis of prospectively collected ovarian high-grade serous cancer samples and appropriate normal precursor samples under tight ischemic control. They identify tumor-associated signaling pathways and mitotic and cyclin-dependent kinases as key oncogenic drivers potentially related to chromosomal instability.

Published
2020
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4. Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma

Author

Yuxing Liao, Meghan C. Burke, Donghui Tan, Xiaoyu Song, Lauren C. Tang, Elizabeth R. Duffy, Shayan C. Avanessian, Daniel Cui Zhou, Maureen Dyer, Sara R. Savage, Jennifer M. Eschbacher, Shaleigh Smith, Alex Webster, Alicia Francis, Kelly V. Ruggles, Christopher R. Kinsinger, Shirley Tsang, Melissa Borucki, Nancy Roche, Pei Wang, Qing Kay Li, David Chesla, Ronald Matteotti, Zeynep H. Gümüş, Kai Li, Kei Suzuki, Thomas L. Bauer, Lori J. Sokoll, John McGee, Marcin J. Domagalski, Ki Sung Um, Tara Hiltke, Hai-Quan Chen, Hongwei Liu, Eric E. Schadt, Antonio Colaprico, Alyssa Charamut, Lijun Chen, Emily Kawaler, Ramani B. Kothadia, Mehdi Mesri, Jiayi Ji, Simina M. Boca, Myvizhi Esai Selvan, Emily S. Boja, Xi Chen, Shuang Cai, Kim Elburn, Samuel H. Payne, George D. Wilson, Peter B. McGarvey, Chelsea J. Newton, Felipe da Veiga Leprevost, Uma Velvulou, Tara Skelly, Corbin D. Jones, Michael J. Birrer, Steven A. Carr, Erik J. Bergstrom, Jeffrey R. Whiteaker, Michael H.A. Roehrl, Gad Getz, Tanya Krubit, Zhen Zhang, Yan Shi, Lili Blumenberg, Melanie A. MacMullan, Song Cao, Zhiao Shi, Weiping Ma, Chet Birger, Karl R. Clauser, Runyu Hong, Shankha Satpathy, Andrii Karnuta, Boris Reva, Barbara Hindenach, Matthew J. Ellis, Amanda G. Paulovich, Michael C. Wendl, Bing Zhang, Marina A. Gritsenko, Matthew A. Wyczalkowski, Stacey Gabriel, Michael A. Gillette, Jacob J. Day, Maciej Wiznerowicz, Stephen E. Stein, Ewa P. Malc, Robert J. Welsh, Sunita Shankar, Brian J. Druker, Li Ding, Lijun Yao, David J. Clark, Małgorzata Wojtyś, Dmitry Rykunov, Eugene S. Fedorov, Linda Hannick, Andrew K. Godwin, Sailaja Mareedu, Pushpa Hariharan, Mary Beth Beasley, Stephanie De Young, Arul M. Chinnaiyan, Robert Zelt, Mathangi Thiagarajan, Munziba Khan, Suhas Vasaikar, Tao Liu, Karin D. Rodland, Katherine A. Hoadley, Wen-Wei Liang, Ana I. Robles, Dana R. Valley, Sanford P. Markey, Mikhail Krotevich, David I. Heiman, Piotr A. Mieczkowski, Galen Hostetter, Liqun Qi, Yige Wu, Hui Zhang, Liang-Bo Wang, Nathan Edwards, Ramaswamy Govindan, Yifat Geffen, Seema Chugh, Alexey I. Nesvizhskii, Karen A. Ketchum, Pankaj Vats, Matthew E. Monroe, Marcin Cieslik, Yingwei Hu, Karsten Krug, Yosef E. Maruvka, Yize Li, Ratna R. Thangudu, William W. Maggio, Sandra Cottingham, Saravana M. Dhanasekaran, Wenke Liu, Hua Sun, Sonya Carter, Volodymyr Sovenko, M. Harry Kane, Annette Marrero-Oliveras, Barbara Pruetz, Amy M. Perou, Gilbert S. Omenn, Azra Krek, Olga Potapova, Michael S. Noble, Daniel W. Chan, Seungyeul Yoo, Eric J. Burks, Bo Wen, William Bocik, Michael Vernon, Henry Rodriguez, James Suh, Scott D. Jewell, MacIntosh Cornwell, Richard D. Smith, Chandan Kumar-Sinha, Halina M. Krzystek, Daniel C. Rohrer, Tatiana Omelchenko, D. R. Mani, Houston Culpepper, Vladislav A. Petyuk, Meng-Hong Sun, Michelle Chaikin, David Fenyö, Rahul Mannan, Bartosz Kubisa, Rohit Mehra, Rajwanth R. Veluswamy, Umut Ozbek, Michael Schnaubelt, Francesca Petralia, Elena V. Ponomareva, Rashna Madan, Pamela Grady, Karna Robinson, and Negin Vatanian

Subjects
0303 health sciences, Phosphoproteomics, Genomics, Environmental exposure, Computational biology, Biology, Proteomics, Proteogenomics, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Neutrophil degranulation, medicine, KRAS, 030217 neurology & neurosurgery, 030304 developmental biology, Epigenomics
Abstract

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.

Published
2020
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5. Proteogenomic Characterization of Endometrial Carcinoma

Author

David J. Clark, Jiayi Ji, Beom-Jun Kim, Doug W. Chan, Zhen Zhang, Kim Elburn, Munziba Khan, Katherine Fuh, Katherine A. Hoadley, Jeffrey R. Whiteaker, Peter B. McGarvey, Dana R. Valley, Douglas A. Levine, Sanford P. Markey, Hui Zhang, Tanya Krubit, Christopher R. Kinsinger, Hui Yin Chang, Yuxing Liao, Karen A. Ketchum, Piotr A. Mieczkowski, Pankaj Vats, Matthew E. Monroe, Donghui Tan, Alex Webster, Chet Birger, Kai Li, Ramani Kothadia, Saravana M. Dhanasekaran, Sara R. Savage, Karsten Krug, Marcin Jędryka, Matthew L. Anderson, Alyssa Charamut, Alexander R. Pico, Amanda G. Paulovich, Karna Robinson, Hua Zhou, John McGee, Sean J.I. Beecroft, Amanda E. Oliphant, Annette Marrero-Oliveras, Dmitry Rykunov, Shuang Cai, Francesmary Modugno, Marcin J. Domagalski, Emily Kawaler, Mehdi Mesri, Dmitry M. Avtonomov, Milan G. Chheda, Sue Hilsenbeck, Gilbert S. Omenn, Emek Demir, Rebecca I. Montgomery, Qingsong Gao, Azra Krek, Eric E. Schadt, Li Ding, George D. Wilson, Stephen E. Stein, David Chesla, Gad Getz, Negin Vatanian, Thomas F. Westbrook, Deborah DeLair, David I. Heiman, Karl R. Clauser, Rafal Matkowski, Lori J. Sokoll, Uma Borate, Antonio Colaprico, Jin Chen, Eric J. Jaehnig, Karin D. Rodland, Richard D. Smith, Linda Hannick, Uma Velvulou, Shannon Richey, Andrzej Czekański, Bing Zhang, Arul M. Chinnaiyan, Robert Zelt, Daniel J. Geiszler, Emily L. Hoskins, Ronald J. Moore, Pushpa Hariharan, Suhas Vasaikar, Jason E. McDermott, Yige Wu, Anna Malovannaya, Brian J. Druker, Jeffrey W. Tyner, Yan Shi, Lili Blumenberg, Jamie Moon, Cristina E. Tognon, Chandan Kumar-Sinha, Nathan Edwards, Yifat Geffen, Barbara Hindenach, Matthew J. Ellis, Zhi Li, Michael Schnaubelt, David C. Wheeler, Tara Skelly, Ewa P. Malc, Shrabanti Chowdhury, Andrew K. Godwin, Zhiao Shi, Francesca Petralia, Lin Chen, Scott D. Jewell, Daniel C. Rohrer, Elie Traer, Michael Ittmann, Shankha Satpathy, Marcin Cieslik, Weiping Ma, Daniel Cui Zhou, Maureen Dyer, Boris Reva, Rashna Madan, William Bocik, Stacey Gabriel, Stephanie De Young, Yosef E. Maruvka, Sandra Cottingham, Pamela Grady, D. R. Mani, Houston Culpepper, Meenakshi Anurag, Michael T. Lewis, Anupriya Agarwal, Felipe D. Leprevost, Jonathan C. Jarman, Michael Vernon, Henry Rodriguez, Matthew A. Wyczalkowski, Rui Zhao, Vladislav A. Petyuk, Michelle Chaikin, James Suh, Daniel W. Chan, Bo Wen, Patricia Castro, Alexey I. Nesvizhskii, Chia-Feng Tsai, Grace Zhao, Alicia Francis, Feng Chen, Mathangi Thiagarajan, Pei Wang, Marina A. Gritsenko, Anna Calinawan, David G. Mutch, Melissa Borucki, Xi Steven Chen, Guo Ci Teo, Peter Dottino, Corbin D. Jones, Michael J. Birrer, Ying Wang, Meghan C. Burke, MacIntosh Cornwell, Song Cao, Rosalie K. Chu, Larisa Polonskaya, Samuel H. Payne, Darlene Tansil, Yongchao Dou, David Fenyö, Kelly V. Ruggles, Qing Kay Li, Yuping Zhang, James J. Hsieh, Andy T. Kong, Ana I. Robles, Emily S. Boja, Chelsea J. Newton, Steven A. Carr, Sandra Cerda, Runyu Hong, Jacob J. Day, Sailaja Mareedu, Jan Lubinski, Galen Hostetter, Liqun Qi, Yize Li, Chen Huang, Liang-Bo Wang, Tao Liu, Renee Karabon, Paul D. Piehowski, Samuel L. Pugh, Maciej Wiznerowicz, Ratna R. Thangudu, Wenke Liu, Jayson B. Field, Sonya Carter, Ki Sung Um, Hongwei Liu, Alla Karpova, Yuriy Zakhartsev, Amy M. Perou, Michael S. Noble, Rajiv Dhir, Nancy Roche, Sunantha Sethuraman, Tara Hiltke, Lijun Chen, Xiaoyu Song, Elizabeth R. Duffy, Robert Edwards, Yingwei Hu, John A. Martignetti, Simina M. Boca, Michael A. Gillette, and David W Adams

Subjects
Epithelial-Mesenchymal Transition, Proteome, Druggability, Biology, Proteomics, Genomic Instability, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigens, Neoplasm, medicine, Animals, Humans, Phosphorylation, 030304 developmental biology, Feedback, Physiological, 0303 health sciences, Endometrial cancer, Carcinoma, Wnt signaling pathway, Cancer, Acetylation, medicine.disease, Proteogenomics, Endometrial Neoplasms, Gene Expression Regulation, Neoplastic, MicroRNAs, Serous fluid, Histone, Cancer research, biology.protein, Female, Transcriptome, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Microsatellite Repeats, Signal Transduction
Abstract

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.

Published
2020
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6. Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma

Author

David J. Clark, Jianbo Pan, Gerald W. Hart, Katherine A. Hoadley, Negin Vatanian, Shuang Cai, Yige Wu, Felipe da Veiga Leprevost, A. Ari Hakimi, Sanford P. Markey, Thomas F. Westbrook, Maciej Wiznerowicz, Nathan Edwards, Alla Y. Karpova, Sohini Sengupta, Marcin Cieslik, Samuel H. Payne, Xi Steven Chen, Guo Ci Teo, Jin Chen, Boris Reva, Corbin D. Jones, Michael J. Birrer, Ying Wang, Kelly V. Ruggles, Doug W. Chan, John McGee, Marcin J. Domagalski, Song Cao, Linda Hannick, Christopher R. Kinsinger, David I. Heiman, Jennifer M. Eschbacher, Munziba Khan, Jason E. McDermott, Dmitry M. Avtonomov, Sue Hilsenbeck, Qing Kay Li, Jiayi Ji, Emek Demir, Rebecca I. Montgomery, Qingsong Gao, Beom-Jun Kim, Xiaoyu Song, Karl R. Clauser, Christian P. Pavlovich, Richard D. Smith, Maureen Dyer, Jeffrey W. Tyner, Amy M. Perou, Yuping Zhang, Dana R. Valley, George D. Wilson, Shiyong Ma, Minghui Ao, Jiang Qian, Umut Ozbek, Melissa Borucki, Zhi Li, Michael Schnaubelt, Chen Huang, Piotr A. Mieczkowski, Francesca Petralia, Abdul Samad Hashimi, Hui Yin Chang, Liang-Bo Wang, Matthew E. Monroe, Peter B. McGarvey, Tao Liu, Karen A. Ketchum, Hui Zhang, Bing Zhang, D. R. Mani, Houston Culpepper, Hua Zhou, Saravana M. Dhanasekaran, Paul D. Piehowski, Zhidong Tu, Brian J. Druker, Ki Sung Um, Zhiao Shi, Uma Borate, Uma Velvulou, Michael Ittmann, Weiping Ma, Steven M. Foltz, Heng Zhu, Stacey Gabriel, Hongwei Liu, Ramani B. Kothadia, Lin Chen, Ewa P. Malc, Marina A. Gritsenko, Jun Zhu, David Chesla, Lori J. Sokoll, Stephen E. Stein, Andrzej Antczak, Matthew L. Anderson, Alyssa Charamut, Pamela Grady, Michael T. Lewis, Shannon Richey, Tanya Krubit, Alexander R. Pico, Kyung-Cho Cho, Daniel C. Rohrer, Francesmary Modugno, Stephanie De Young, Li Ding, Michael Smith, Mathangi Thiagarajan, Alexey I. Nesvizhskii, Shrabanti Chowdhury, Noam D. Beckmann, Kimberly R. Holloway, Ratna R. Thangudu, Sherri R. Davies, Tung-Shing M. Lih, Nicole Tignor, Anna Calinawan, Meghan C. Burke, Karna Robinson, Chet Birger, Shalin Patel, Antonio Colaprico, Sarah Keegan, Daniel J. Geiszler, Scott D. Jewell, William Bocik, Snehal Patil, Pei Wang, MacIntosh Cornwell, Emily Kawaler, Seungyeul Yoo, Jasmine Huang, Vladislav A. Petyuk, Ross Bremner, Donghui Tan, Stefani N. Thomas, Emily S. Boja, Anna Malovannaya, Xi Chen, Wenke Liu, Eric E. Schadt, Shankha Satpathy, Nancy Roche, Rajiv Dhir, Cristina E. Tognon, Michelle Chaikin, Gabriel Bromiński, Daniel C. Zhou, Yifat Geffen, Tara Skelly, Jacob J. Day, Sunantha Sethuraman, Sonya Carter, Zhen Zhang, Selim Kalayci, Michael Vernon, Zeynep H. Gümüş, Kai Li, Barbara Hindenach, Matthew J. Ellis, Meenakshi Anurag, David C. Wheeler, Sailaja Mareedu, Andy T. Kong, Arul M. Chinnaiyan, Robert Zelt, Annette Marrero-Oliveras, Henry Rodriguez, James Suh, Anupriya Agarwal, David Fenyö, Galen Hostetter, Liqun Qi, Matthew A. Wyczalkowski, W. Marston Linehan, Tara Hiltke, Feng Chen, Lijun Chen, Jan Lubinski, Chelsea J. Newton, Steven A. Carr, Tatiana Omelchenko, Gilbert S. Omenn, Karsten Krug, Ana I. Robles, Azra Krek, Runyu Hong, Milan G. Chheda, Yize Li, Yan Shi, Lili Blumenberg, Ruiyang Liu, Karin D. Rodland, Hua Sun, Kim Elburn, Jeffrey R. Whiteaker, Christopher J. Ricketts, Gaddy Getz, Daniel W. Chan, Bo Wen, Robert Edwards, Patricia Castro, Yingwei Hu, Pushpa Hariharan, Simina M. Boca, Darlene Tansil, Phillip M. Pierorazio, Yosef E. Maruvka, Sandra Cottingham, James J. Hsieh, Amanda G. Paulovich, Barbara Pruetz, Michael A. Gillette, Yihao Lu, Dmitry Rykunov, Mehdi Mesri, Marc M. Loriaux, Reyka G Jayasinghe, and Suhas Vasaikar

Subjects
Adult, Male, Cell, Computational biology, Biology, Proteomics, Disease-Free Survival, Oxidative Phosphorylation, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, medicine, Biomarkers, Tumor, Tumor Microenvironment, Humans, Exome, Phosphorylation, Carcinoma, Renal Cell, 030304 developmental biology, Epigenomics, Aged, Proteogenomics, Aged, 80 and over, 0303 health sciences, Tumor microenvironment, Genome, Human, Phosphoproteomics, Middle Aged, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Clear cell renal cell carcinoma, medicine.anatomical_structure, Female, 030217 neurology & neurosurgery, Signal Transduction
Abstract

SUMMARY To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale proteogenomic analysis of ccRCC to discern the functional impact of genomic alterations and provides evidence for rational treatment selection stemming from ccRCC pathobiology., Graphical Abstract, In Brief Comprehensive proteogenomic characterization in 103 treatment-naive clear cell renal cell carcinoma patient samples highlights tumor-specific alterations at the proteomic level that are unrevealed by transcriptomic profiling and proposes a revised subtyping scheme based on integrated omics analysis.

Published
2020
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7. Before and After: Comparison of Legacy and Harmonized TCGA Genomic Data Commons’ Data

Author

Peter W. Laird, Katherine A. Hoadley, A. Gordon Robertson, Denise Brooks, Hu Chen, John A. Demchok, Matthew H. Bailey, Jean C. Zenklusen, Hui Shen, Roy Tarnuzzer, Daniela S. Gerhard, Ina Felau, Kyle M. Hernandez, Michael S. Noble, Tiago C. Silva, Michael K A Mensah, Zhining Wang, Theo A. Knijnenburg, Matthew A. Wyczalkowski, Reyka G Jayasinghe, Liming Yang, Han Liang, David I. Heiman, Liang-Bo Wang, Andrew D. Cherniack, Li Ding, Wanding Zhou, Sharon Gaheen, Galen F. Gao, Saianand Balu, Andrew J. Mungall, Rehan Akbani, Joel S. Parker, Sheila Reynolds, Z. Zhang, Anab Kemal, and Benjamin P. Berman

Subjects
0303 health sciences, Histology, Computer science, Genomic data, Cell Biology, Computational biology, Pathology and Forensic Medicine, Omics data, 03 medical and health sciences, 0302 clinical medicine, Mirna expression, Cancer genome, DNA methylation, Degree of similarity, Commons, 030217 neurology & neurosurgery, 030304 developmental biology, Reference genome
Abstract

We present a systematic analysis of the effects of synchronizing a large-scale, deeply characterized, multi-omic dataset to the current human reference genome, using updated software, pipelines, and annotations. For each of 5 molecular data platforms in The Cancer Genome Atlas (TCGA)—mRNA and miRNA expression, single nucleotide variants, DNA methylation and copy number alterations—comprehensive sample, gene, and probe-level studies were performed, towards quantifying the degree of similarity between the ‘legacy’ GRCh37 (hg19) TCGA data and its GRCh38 (hg38) version as ‘harmonized’ by the Genomic Data Commons. We offer gene lists to elucidate differences that remained after controlling for confounders, and strategies to mitigate their impact on biological interpretation. Our results demonstrate that the hg19 and hg38 TCGA datasets are very highly concordant, promote informed use of either legacy or harmonized omics data, and provide a rubric that encourages similar comparisons as new data emerge and reference data evolve. Gao et al. performed a systematic analysis of the effects of synchronizing the large-scale, widely used, multi-omic dataset of The Cancer Genome Atlas to the current human reference genome. For each of the five molecular data platforms assessed, they demonstrated a very high concordance between the ‘legacy’ GRCh37 (hg19) TCGA data and its GRCh38 (hg38) version as ‘harmonized’ by the Genomic Data Commons.

Published
2019
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