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1. Genomic characterization of cervical lymph node metastases in papillary thyroid carcinoma following the Chornobyl accident

Author: Lindsay M. Morton, Olivia W. Lee, Danielle M. Karyadi, Tetiana I. Bogdanova, Chip Stewart, Stephen W. Hartley, Charles E. Breeze, Sara J. Schonfeld, Elizabeth K. Cahoon, Vladimir Drozdovitch, Sergii Masiuk, Mykola Chepurny, Liudmyla Yu Zurnadzhy, Jieqiong Dai, Marko Krznaric, Meredith Yeager, Amy Hutchinson, Belynda D. Hicks, Casey L. Dagnall, Mia K. Steinberg, Kristine Jones, Komal Jain, Ben Jordan, Mitchell J. Machiela, Eric T. Dawson, Vibha Vij, Julie M. Gastier-Foster, Jay Bowen, Kiyohiko Mabuchi, Maureen Hatch, Amy Berrington de Gonzalez, Gad Getz, Mykola D. Tronko, Gerry A. Thomas, and Stephen J. Chanock
Subjects: Science
Abstract: Abstract Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.
Published: 2024
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2. Is It Just Dumb Luck? The Challenge of Getting Access to Public Records Related to Smart City Technology

Author: Amy Kristin Sanders, Daxton "Chip" Stewart, and Steven Molchanov
Subjects: Information resources (General), ZA3040-5185, Political institutions and public administration (General), JF20-2112
Abstract: Many state and local governments have begun to rely heavily on Smart City technologies, including license plate readers, gun-shot detection equipment, wastewater monitoring tools, and more. But the public often has little oversight with regard to their purchase, installation, and use. We analyze public records laws and relevant case law to examine whether the laws provide access to records about, and produced by, Smart City technologies. Even in states that broadly define “public record,” officials regularly rely on exemptions—often citing law enforcement or privacy concerns—to deny access. Further, many Smart City technologies have not been addressed by the legislatures and courts, but legislation and litigation involving two technologies (police body-worn cameras and police dash cameras) have advanced—offering some optimism.
Published: 2024
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3. The Law and Convergent Journalism

Author: Chip Stewart, Daxton R., primary
Published: 2023
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4. Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma

Author: Chunyang Bao, Richard W. Tourdot, Gregory J. Brunette, Chip Stewart, Lili Sun, Hideo Baba, Masayuki Watanabe, Agoston T. Agoston, Kunal Jajoo, Jon M. Davison, Katie S. Nason, Gad Getz, Kenneth K. Wang, Yu Imamura, Robert Odze, Adam J. Bass, Matthew D. Stachler, and Cheng-Zhong Zhang
Subjects: Science
Abstract: Abstract The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.
Published: 2023
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5. Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes

Author: Mark Bustoros, Shankara Anand, Romanos Sklavenitis-Pistofidis, Robert Redd, Eileen M. Boyle, Benny Zhitomirsky, Andrew J. Dunford, Yu-Tzu Tai, Selina J. Chavda, Cody Boehner, Carl Jannes Neuse, Mahshid Rahmat, Ankit Dutta, Tineke Casneuf, Raluca Verona, Efstathis Kastritis, Lorenzo Trippa, Chip Stewart, Brian A. Walker, Faith E. Davies, Meletios-Athanasios Dimopoulos, P. Leif Bergsagel, Kwee Yong, Gareth J. Morgan, François Aguet, Gad Getz, and Irene M. Ghobrial
Subjects: Science
Abstract: Existing clinical models cannot fully capture smoldering multiple myeloma (SMM) heterogeneity. Here, integration of 42 genetic alterations from 214 SMM patients using an unsupervised binary matrix factorization clustering approach results in the identification of 6 distinct molecular and clinical subtypes.
Published: 2022
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6. Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant

Author: Tarek H. Mouhieddine, Adam S. Sperling, Robert Redd, Jihye Park, Matthew Leventhal, Christopher J. Gibson, Salomon Manier, Amin H. Nassar, Marzia Capelletti, Daisy Huynh, Mark Bustoros, Romanos Sklavenitis-Pistofidis, Sabrin Tahri, Kalvis Hornburg, Henry Dumke, Muhieddine M. Itani, Cody J. Boehner, Chia-Jen Liu, Saud H. AlDubayan, Brendan Reardon, Eliezer M. Van Allen, Jonathan J. Keats, Chip Stewart, Shaadi Mehr, Daniel Auclair, Robert L. Schlossman, Nikhil C. Munshi, Kenneth C. Anderson, David P. Steensma, Jacob P. Laubach, Paul G. Richardson, Jerome Ritz, Benjamin L. Ebert, Robert J. Soiffer, Lorenzo Trippa, Gad Getz, Donna S. Neuberg, and Irene M. Ghobrial
Subjects: Science
Abstract: Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.
Published: 2020
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7. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

Author: Esther Rheinbay, Morten Muhlig Nielsen, Federico Abascal, Jeremiah Wala, Ofer Shapira, Grace Tiao, Henrik Hornshøj, Julian M. Hess, Randi Istrup Juul, Ziao Lin, Lars Feuerbach, Radhakrishnan Sabarinathan, Tobias Madsen, Jaegil Kim, Loris Mularoni, Shimin Shuai, Andrés Lanzós, Carl Herrmann, Yosef E. Maruvka, Ciyue Shen, Samirkumar B. Amin, Pratiti Bandopadhayay, Johanna Bertl, Keith A. Boroevich, John Busanovich, Joana Carlevaro-Fita, Dimple Chakravarty, Calvin Wing Yiu Chan, David Craft, Priyanka Dhingra, Klev Diamanti, Nuno A. Fonseca, Abel Gonzalez-Perez, Qianyun Guo, Mark P. Hamilton, Nicholas J. Haradhvala, Chen Hong, Keren Isaev, Todd A. Johnson, Malene Juul, André Kahles, Abdullah Kahraman, Youngwook Kim, Jan Komorowski, Kiran Kumar, Sushant Kumar, Donghoon Lee 0006, Kjong-Van Lehmann, Yilong Li, Eric Minwei Liu, Lucas Lochovsky, Keunchil Park, Oriol Pich, Nicola D. Roberts, Gordon Saksena, Steven E. Schumacher, Nikos Sidiropoulos, Lina Sieverling, Nasa Sinnott-Armstrong, Chip Stewart, David Tamborero, Jose M. C. Tubio, Husen M. Umer, Liis Uusküla-Reimand, Claes Wadelius, Lina Wadi, Xiaotong Yao, Cheng-Zhong Zhang, Jing Zhang 0062, James E. Haber, Asger Hobolth, Marcin Imielinski, Manolis Kellis, Michael S. Lawrence, Christian von Mering, Hidewaki Nakagawa, Benjamin J. Raphael, Mark A. Rubin, Chris Sander, Lincoln D. Stein, Joshua M. Stuart, Tatsuhiko Tsunoda, David A. Wheeler, Rory Johnson, Jüri Reimand, Mark Gerstein, Ekta Khurana, Peter J. Campbell, Núria López-Bigas, Gary D. Bader, Jonathan Barenboim, Rameen Beroukhim, Søren Brunak, Ken Chen, Jung Kyoon Choi, Jordi Deu-Pons, J. Lynn Fink, Joan Frigola, Carlo Gambacorti Passerini, Dale W. Garsed, Gad Getz, Ivo Glynne Gut, David Haan, Arif Ozgun Harmanci, Mohamed Helmy, Ermin Hodzic, José M. G. Izarzugaza, Jong K. Kim, Jan O. Korbel, Erik Larsson, Shantao Li, Xiaotong Li, Shaoke Lou, Kathleen Marchal, Iñigo Martincorena, Alexander Martínez-Fundichely, Patrick D. McGillivray, William Meyerson, Ferran Muiños, Marta Paczkowska, Kiejung Park, Jakob Skou Pedersen, Tirso Pons, Sergio Pulido-Tamayo, Iker Reyes-Salazar, Matthew A. Reyna, Carlota Rubio-Perez, Süleyman Cenk Sahinalp, Leonidas Salichos, Mark Shackleton, Raunak Shrestha, Alfonso Valencia, Miguel Vazquez, Lieven P. C. Verbeke, Jiayin Wang, Jonathan Warrell, Sebastian M. Waszak, Joachim Weischenfeldt, Guanming Wu, Jun Yu, Xuanping Zhang, Yan Zhang 0032, Zhongming Zhao, Lihua Zou, Kadir C. Akdemir, Eva G. Alvarez, Adrian Baez-Ortega, Paul C. Boutros, David D. L. Bowtell, Benedikt Brors, Kathleen H. Burns, Kin Chan, Isidro Cortés-Ciriano, Ana Dueso-Barroso, Andrew J. Dunford, Paul A. Edwards, Xavier Estivill, Dariush Etemadmoghadam, Milana Frenkel-Morgenstern, Dmitry A. Gordenin, Barbara Hutter, David T. W. Jones, Young Seok Ju, Marat D. Kazanov, Leszek J. Klimczak, Youngil Koh, Eunjung Alice Lee, Jake June-Koo Lee, Andy G. Lynch, Geoff MacIntyre, Florian Markowetz, Matthew Meyerson, Satoru Miyano, Fabio C. P. Navarro, Stephan Ossowski, Peter J. Park, John V. Pearson, Montserrat Puiggròs, Karsten Rippe, Steven A. Roberts, Bernardo Rodriguez-Martin, Ralph Scully, David Torrents, Izar Villasante, Nicola Waddell, Jeremiah A. Wala, Lixing Yang, Sung-Soo Yoon, and Jorge Zamora
Published: 2020
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8. Ghosted by Government

Author: Amy Kristin Sanders and Daxton "Chip" Stewart
Subjects: Information resources (General), ZA3040-5185, Political institutions and public administration (General), JF20-2112
Abstract: Public records laws across the United States operate under the presumption that citizens should have access to government records, but obtaining this information is not always a simple undertaking. Although state public records laws vary, only a few establish a requirement that government entities acknowledge the existence of a request. And while some state laws mandate a time limit within which entities are supposed to produce records or issue a denial, those limits vary considerably from the specific three business days to the vague requirement of promptness. We analyzed these requirements in the 50 states and recommend policy changes that would hold government entities accountable to requestors and create a more level playing field for citizens seeking public records that should presumptively be open.
Published: 2021

9. Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion

Author: Kirsty Wienand, Bjoern Chapuy, Chip Stewart, Andrew J. Dunford, David Wu, Jaegil Kim, Atanas Kamburov, Timothy R. Wood, Fathima Zumla Cader, Matthew D. Ducar, Aaron R. Thorner, Anwesha Nag, Alexander T. Heubeck, Michael J. Buonopane, Robert A. Redd, Kamil Bojarczuk, Lee N. Lawton, Philippe Armand, Scott J. Rodig, Jonathan R. Fromm, Gad Getz, and Margaret A. Shipp
Subjects: Specialties of internal medicine, RC581-951
Abstract: Abstract: Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands. To define genetic mechanisms of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole-exome sequencing of flow cytometry–sorted HRS cells from 23 excisional biopsies of newly diagnosed cHLs, including 8 Epstein-Barr virus–positive (EBV+) tumors. We identified significantly mutated cancer candidate genes (CCGs) as well as somatic copy number alterations and structural variations and characterized their contribution to disease-defining immune evasion mechanisms and nuclear factor κB (NF-κB), JAK/STAT, and PI3K signaling pathways. EBV– cHLs had a higher prevalence of genetic alterations in the NF-κB and major histocompatibility complex class I antigen presentation pathways. In this young cHL cohort (median age, 26 years), we identified a predominant mutational signature of spontaneous deamination of cytosine- phosphate-guanines (“Aging”), in addition to apolipoprotein B mRNA editing catalytic polypeptide-like, activation-induced cytidine deaminase, and microsatellite instability (MSI)–associated hypermutation. In particular, the mutational burden in EBV– cHLs was among the highest reported, similar to that of carcinogen-induced tumors. Together, the overall high mutational burden, MSI-associated hypermutation, and newly identified genetic alterations represent additional potential bases for the efficacy of PD-1 blockade in cHL. Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1 mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases.
Published: 2019
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10. A (fire)cloud-based DNA methylation data preprocessing and quality control platform

Author: Divy Kangeyan, Andrew Dunford, Sowmya Iyer, Chip Stewart, Megan Hanna, Gad Getz, and Martin J. Aryee
Subjects: DNA methylation, Cloud computing, Bioinformatics workflows, Quality control analysis, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract: Abstract Background Bisulfite sequencing allows base-pair resolution profiling of DNA methylation and has recently been adapted for use in single-cells. Analyzing these data, including making comparisons with existing data, remains challenging due to the scale of the data and differences in preprocessing methods between published datasets. Results We present a set of preprocessing pipelines for bisulfite sequencing DNA methylation data that include a new R/Bioconductor package, scmeth, for a series of efficient QC analyses of large datasets. The pipelines go from raw data to CpG-level methylation estimates and can be run, with identical results, either on a single computer, in an HPC cluster or on Google Cloud Compute resources. These pipelines are designed to allow users to 1) ensure reproducibility of analyses, 2) achieve scalability to large whole genome datasets with 100 GB+ of raw data per sample and to single-cell datasets with thousands of cells, 3) enable integration and comparison between user-provided data and publicly available data, as all samples can be processed through the same pipeline, and 4) access to best-practice analysis pipelines. Pipelines are provided for whole genome bisulfite sequencing (WGBS), reduced representation bisulfite sequencing (RRBS) and hybrid selection (capture) bisulfite sequencing (HSBS). Conclusions The workflows produce data quality metrics, visualization tracks, and aggregated output for further downstream analysis. Optional use of cloud computing resources facilitates analysis of large datasets, and integration with existing methylome profiles. The workflow design principles are applicable to other genomic data types.
Published: 2019
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11. Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer

Author: Arvind Ravi, Matthew D. Hellmann, Monica B. Arniella, Mark Holton, Samuel S. Freeman, Vivek Naranbhai, Chip Stewart, Ignaty Leshchiner, Jaegil Kim, Yo Akiyama, Aaron T. Griffin, Natalie I. Vokes, Mustafa Sakhi, Vashine Kamesan, Hira Rizvi, Biagio Ricciuti, Patrick M. Forde, Valsamo Anagnostou, Jonathan W. Riess, Don L. Gibbons, Nathan A. Pennell, Vamsidhar Velcheti, Subba R. Digumarthy, Mari Mino-Kenudson, Andrea Califano, John V. Heymach, Roy S. Herbst, Julie R. Brahmer, Kurt A. Schalper, Victor E. Velculescu, Brian S. Henick, Naiyer Rizvi, Pasi A. Jänne, Mark M. Awad, Andrew Chow, Benjamin D. Greenbaum, Marta Luksza, Alice T. Shaw, Jedd Wolchok, Nir Hacohen, Gad Getz, and Justin F. Gainor
Subjects: Genetics
Abstract: Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.
Published: 2023
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12. MinimuMM-seq: Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

Author: Ankit K. Dutta, Jean-Baptiste Alberge, Elizabeth D. Lightbody, Cody J. Boehner, Andrew Dunford, Romanos Sklavenitis-Pistofidis, Tarek H. Mouhieddine, Annie N. Cowan, Nang Kham Su, Erica M. Horowitz, Hadley Barr, Laura Hevenor, Jenna B. Beckwith, Jacqueline Perry, Amanda Cao, Ziao Lin, Frank K. Kuhr, Richard G. Del Mastro, Omar Nadeem, Patricia T. Greipp, Chip Stewart, Daniel Auclair, Gad Getz, and Irene M. Ghobrial
Subjects: Oncology
Abstract: Abstract Multiple myeloma (MM) develops from well-defined precursor stages; however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. We enumerated circulating tumor cells (CTC) from 261 patients (84 monoclonal gammopathy of undetermined significance, 155 smoldering multiple myeloma, and 22 MM), with neoplastic cells detected in 84%. We developed a novel approach, MinimuMM-seq, which enables the detection of translocations and copy-number abnormalities through whole-genome sequencing of highly pure CTCs. Application to CTCs in a cohort of 51 patients, 24 with paired BM, was able to detect 100% of clinically reported BM biopsy events and could replace molecular cytogenetics for diagnostic yield and risk classification. Longitudinal sampling of CTCs in 8 patients revealed major clones could be tracked in the blood, with clonal evolution and shifting dynamics of subclones over time. Our findings provide proof of concept that CTC detection and genomic profiling could be used clinically for monitoring and managing disease in MM. Significance: In this study, we established an approach enabling the enumeration and sequencing of CTCs to replace standard molecular cytogenetics. CTCs harbored the same pathognomonic MM abnormalities as BM plasma cells. Longitudinal sampling of serial CTCs was able to track clonal dynamics over time and detect the emergence of high-risk genetic subclones.
Published: 2023
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13. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

Author: Erin M. Parry, Ignaty Leshchiner, Romain Guièze, Connor Johnson, Eugen Tausch, Sameer A. Parikh, Camilla Lemvigh, Julien Broséus, Sébastien Hergalant, Conor Messer, Filippo Utro, Chaya Levovitz, Kahn Rhrissorrakrai, Liang Li, Daniel Rosebrock, Shanye Yin, Stephanie Deng, Kara Slowik, Raquel Jacobs, Teddy Huang, Shuqiang Li, Geoff Fell, Robert Redd, Ziao Lin, Binyamin A. Knisbacher, Dimitri Livitz, Christof Schneider, Neil Ruthen, Liudmila Elagina, Amaro Taylor-Weiner, Bria Persaud, Aina Martinez, Stacey M. Fernandes, Noelia Purroy, Annabelle J. Anandappa, Jialin Ma, Julian Hess, Laura Z. Rassenti, Thomas J. Kipps, Nitin Jain, William Wierda, Florence Cymbalista, Pierre Feugier, Neil E. Kay, Kenneth J. Livak, Brian P. Danysh, Chip Stewart, Donna Neuberg, Matthew S. Davids, Jennifer R. Brown, Laxmi Parida, Stephan Stilgenbauer, Gad Getz, Catherine J. Wu, Dana-Farber Cancer Institute [Boston], Broad Institute [Cambridge], Harvard University-Massachusetts Institute of Technology (MIT), Harvard Medical School [Boston] (HMS), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), CHU Clermont-Ferrand, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), Universität Ulm - Ulm University [Ulm, Allemagne], Mayo Clinic [Rochester], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), IBM Thomas J. Watson Research Center, IBM, Moores Cancer Center [La Jolla], School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Service d'Hématologie [CHRU Nancy], Massachusetts General Hospital [Boston], and Brigham and Women's Hospital [Boston]
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], General Biochemistry, Genetics and Molecular Biology
Abstract: International audience
Published: 2023
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14. Optimizing event selection with the random grid search.

Author: Pushpalatha C. Bhat, Harrison B. Prosper, Sezen Sekmen, and Chip Stewart
Published: 2018
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15. Evolutionary History of Transformation from Chronic Lymphocytic Leukemia to Richter Syndrome

Author: Erin Michelle Parry, Romain Guieze, Ignaty Leshchiner, Connor Johnson, Eugen Tausch, Sameer A. Parikh, Camilla K Lemvigh, Julien Broséus, Sébastien Hergalant, Connor Messer, Filippo Utro, Chaya Levovitz, Kahn Rhrissorrakrai, Liang Li, Shuqiang Li, Geoffrey G Fell, Robert A. Redd, Ziao Lin, Binyamin A. Knisbacher, Christof Schneider, Stacey M. Fernandes, Julian M. Hess, Laura Z. Rassenti, Thomas J. Kipps, Nitin Jain, William G. Wierda, Florence Cymbalista, Pierre Feugier, Neil E. Kay, Kenneth J Livak, Brian P Danysh, Chip Stewart, Donna S. Neuberg, Matthew S. Davids, Jennifer R. Brown, Laxmi Parida, Stephan Stilgenbauer, Gad Getz, and Catherine J. Wu
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022
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16. The Law and Convergent Journalism

Author: “Chip” Stewart, Daxton R., primary
Published: 2019
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17. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Author: Viktor A. Adalsteinsson, Gavin Ha, Samuel S. Freeman, Atish D. Choudhury, Daniel G. Stover, Heather A. Parsons, Gregory Gydush, Sarah C. Reed, Denisse Rotem, Justin Rhoades, Denis Loginov, Dimitri Livitz, Daniel Rosebrock, Ignaty Leshchiner, Jaegil Kim, Chip Stewart, Mara Rosenberg, Joshua M. Francis, Cheng-Zhong Zhang, Ofir Cohen, Coyin Oh, Huiming Ding, Paz Polak, Max Lloyd, Sairah Mahmud, Karla Helvie, Margaret S. Merrill, Rebecca A. Santiago, Edward P. O’Connor, Seong H. Jeong, Rachel Leeson, Rachel M. Barry, Joseph F. Kramkowski, Zhenwei Zhang, Laura Polacek, Jens G. Lohr, Molly Schleicher, Emily Lipscomb, Andrea Saltzman, Nelly M. Oliver, Lori Marini, Adrienne G. Waks, Lauren C. Harshman, Sara M. Tolaney, Eliezer M. Van Allen, Eric P. Winer, Nancy U. Lin, Mari Nakabayashi, Mary-Ellen Taplin, Cory M. Johannessen, Levi A. Garraway, Todd R. Golub, Jesse S. Boehm, Nikhil Wagle, Gad Getz, J. Christopher Love, and Matthew Meyerson
Subjects: Science
Abstract: Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.
Published: 2017
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18. Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer

Author: Junko Tsuji, Tianyu Li, Albert Grinshpun, Tim Coorens, Douglas Russo, Leilani Anderson, Rebecca Rees, Agostina Nardone, Candace Patterson, Niall J. Lennon, Carrie Cibulskis, Ignaty Leshchiner, Nabihah Tayob, Sara M. Tolaney, Nadine Tung, Donald P. McDonnell, Ian E. Krop, Eric P. Winer, Chip Stewart, Gad Getz, and Rinath Jeselsohn
Subjects: Cancer Research, Treatment Outcome, Receptors, Estrogen, Oncology, Receptor, ErbB-2, Antineoplastic Combined Chemotherapy Protocols, Exome Sequencing, Liquid Biopsy, Humans, Female, Breast Neoplasms, Article
Abstract: Purpose: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. Patients and Methods: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2− advanced breast cancer who progressed on prior ET (N = 36; NCT02448771). Results: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0–7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5–13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment. Conclusions: The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2− breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.
Published: 2022
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19. Secrecy Inc.

Author: Daxton "Chip" Stewart and Amy Kristin Sanders
Subjects: Information resources (General), ZA3040-5185, Political institutions and public administration (General), JF20-2112
Abstract: As governments engage in public-private partnerships, they have devised ways to shield the public’s business from the traditional level scrutiny offered by citizens and journalists, watchdogs of the public trust. The authors propose rethinking public oversight of private vendors doing government business. First, the authors explore the historical and legal background of open records laws. This core purpose is undermined by overly broad interpretations of trade secrets and competitive harm exceptions, a trend exacerbated by the U.S. Supreme Court in a 2019 ruling. The authors demonstrate why public-private collusion to sabotage transparency demands a reinvigorated approach to the quasi-government body doctrine, which has been sharply limited for decades. The authors conclude with recommendations on reversing the trend.
Published: 2019
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20. Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic Gvhd and Candidate GVL Targets

Author: Nicoletta Cieri, Nidhi Hookeri, Kari Stromhaug, Jonathan Stevens, Kameron Kooshesh, Susan Klaeger, Karl R. Clauser, Siranush Sarkizova, David A. Braun, Livius Penter, Giacomo Oliveira, Haesook T. Kim, William J. Lane, Shuqiang Li, Kenneth J. Livak, Vincent T. Ho, Jerome Ritz, Robert J. Soiffer, Derin B. Keskin, Chip Stewart, Alexander Gusev, Gad Getz, and Catherine J. Wu
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022
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21. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

Author: Jan A. Burger, Dan A. Landau, Amaro Taylor-Weiner, Ivana Bozic, Huidan Zhang, Kristopher Sarosiek, Lili Wang, Chip Stewart, Jean Fan, Julia Hoellenriegel, Mariela Sivina, Adrian M. Dubuc, Cameron Fraser, Yulong Han, Shuqiang Li, Kenneth J. Livak, Lihua Zou, Youzhong Wan, Sergej Konoplev, Carrie Sougnez, Jennifer R. Brown, Lynne V. Abruzzo, Scott L. Carter, Michael J. Keating, Matthew S. Davids, William G. Wierda, Kristian Cibulskis, Thorsten Zenz, Lillian Werner, Paola Dal Cin, Peter Kharchencko, Donna Neuberg, Hagop Kantarjian, Eric Lander, Stacey Gabriel, Susan O’Brien, Anthony Letai, David A. Weitz, Martin A. Nowak, Gad Getz, and Catherine J. Wu
Subjects: Science
Abstract: The BTK inhibitor ibrutinib is used to treat chronic lymphocytic leukaemia, however some patients develop resistance to the drug. Here, the authors use genomic analyses to examine the clonal evolution of 5 patients that develop resistance to ibrutinib.
Published: 2016
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22. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma

Author: Marios Giannakis, Xinmeng Jasmine Mu, Sachet A. Shukla, Zhi Rong Qian, Ofir Cohen, Reiko Nishihara, Samira Bahl, Yin Cao, Ali Amin-Mansour, Mai Yamauchi, Yasutaka Sukawa, Chip Stewart, Mara Rosenberg, Kosuke Mima, Kentaro Inamura, Katsuhiko Nosho, Jonathan A. Nowak, Michael S. Lawrence, Edward L. Giovannucci, Andrew T. Chan, Kimmie Ng, Jeffrey A. Meyerhardt, Eliezer M. Van Allen, Gad Getz, Stacey B. Gabriel, Eric S. Lander, Catherine J. Wu, Charles S. Fuchs, Shuji Ogino, and Levi A. Garraway
Subjects: Biology (General), QH301-705.5
Abstract: Large-scale genomic characterization of tumors from prospective cohort studies may yield new insights into cancer pathogenesis. We performed whole-exome sequencing of 619 incident colorectal cancers (CRCs) and integrated the results with tumor immunity, pathology, and survival data. We identified recurrently mutated genes in CRC, such as BCL9L, RBM10, CTCF, and KLF5, that were not previously appreciated in this disease. Furthermore, we investigated the genomic correlates of immune-cell infiltration and found that higher neoantigen load was positively associated with overall lymphocytic infiltration, tumor-infiltrating lymphocytes (TILs), memory T cells, and CRC-specific survival. The association with TILs was evident even within microsatellite-stable tumors. We also found positive selection of mutations in HLA genes and other components of the antigen-processing machinery in TIL-rich tumors. These results may inform immunotherapeutic approaches in CRC. More generally, this study demonstrates a framework for future integrative molecular epidemiology research in colorectal and other malignancies.
Published: 2016
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23. Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma

Author: Caitlin A. Creasy, Yuzhong Jeff Meng, Marie-Andrée Forget, Tatiana Karpinets, Katarzyna Tomczak, Chip Stewart, Carlos A. Torres-Cabala, Shari Pilon-Thomas, Amod A. Sarnaik, James J. Mulé, Levi Garraway, Matias Bustos, Jianhua Zhang, Sapna P. Patel, Adi Diab, Isabella C. Glitza, Cassian Yee, Hussein Tawbi, Michael K. Wong, Jennifer McQuade, Dave S.B. Hoon, Michael A. Davies, Patrick Hwu, Rodabe N. Amaria, Cara Haymaker, Rameen Beroukhim, and Chantale Bernatchez
Subjects: Cancer Research, Lymphocytes, Tumor-Infiltrating, Oncology, Cell- and Tissue-Based Therapy, Tumor Microenvironment, Endothelial Cells, Humans, Neoplasms, Second Primary, Genomics, Immunotherapy, Adoptive, Melanoma, Article
Abstract: Purpose:Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%–50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.Experimental Design:We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.Results:Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved PFS and OS. In contrast, the expression of ELFN1 was enriched in patients with unfavorable response, poor PFS and OS, whereas enhanced methylation of ELFN1 was observed in patients with favorable outcomes. Expression of ELFN1, NGFR, and PDE1C was mainly found in cancer-associated fibroblasts and endothelial cells in tumor tissues across different cancer types in publicly available single-cell RNA sequencing datasets, suggesting a role for elements of the tumor microenvironment in defining the outcome of TIL therapy.Conclusions:Our findings suggest that transcriptional features of melanomas correlate with outcomes after TIL therapy and may provide candidates to guide patient selection.
Published: 2022
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24. Abstract GS2-09: Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations

Author: Kirsten Kubler, Agostina Nardone, Shankara Anand, Daniel Gorvich, Marjolein Droog, Francisco Hermida-Prado, Tara Akshi, Avery S Feit, Gabriella Cohen, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, William J Gibson, Cloud P Paweletz, Eliezer M Van Allen, Flora E van Leeuwen, Petra Nederlof, Harry Hollema, Quang-Dé Nguyen, Marian JE Mourits, Ignaty Leshchiner, Chip Stewart, Ursula A Matulonis, Wilbert Zwart, Yosef E Maruvka, Gad Getz, and Rinath Jeselsohn
Subjects: Cancer Research, Oncology
Abstract: Tamoxifen is widely used in the adjuvant treatment of estrogen receptor–positive (ER+) breast cancer and is an important drug for pre-menopausal women and post-menopausal patients who cannot tolerate aromatase inhibitors. Despite the clear clinical benefit in improving relapse-free and overall survival in these patients, an adverse effect of tamoxifen is a 2- to 7-fold increased risk of uterine cancer (UC) after 2-5 years of treatment. To date, the mechanism of tamoxifen-driven tumorigenesis is not well understood, and preventive approaches are lacking. Here, to molecularly characterize tamoxifen-associated uterine cancers (TA-UCs) and gain insights into their unique evolution, we performed whole-exome sequencing of 21 TA-UCs (discovery cohort) and droplet digital PCR (ddPCR) of an additional 40 TA-UCs (validation cohort) obtained from the ‘Tamoxifen Associated Malignancies: Aspects of Risk’ (TAMARISK) study. In addition, we used in vivo mouse models to: (i) further investigate tamoxifen-activated molecular pathways that may be involved in TA-UC tumorigenesis; and (ii) offer mechanistic insights. Overall, we discovered that TA-UCs were genomically similar to non–TA-UCs from The Cancer Genome Atlas (TCGA) project, with one profound exception: TA-UCs are characterized by a lower-than-expected frequency of mutations in two highly prevalent UC driver genes in the PI3K pathway: PIK3CA (14% [3/21] vs 48% [265/554] in non–TA-UC; P=0.003, Fisher’s exact test; Q=0.02, Benjamini-Hochberg FDR) and PIK3R1 (0%, [0/21] vs 31% [174/554]; P=0.001; Q=0.01). We used ddPCR in the independent TA-UC validation cohort and confirmed the low frequency of mutations in PIK3CA (7.5% [3/40] vs 21% [144/685] in control UCs from the Dana-Farber contribution to the AACR GENIE project; P=0.04). We next performed mouse in vivo studies and demonstrated that tamoxifen activated the PI3K pathway and increased cell proliferation in normal mouse uterine tissue through paracrine and autocrine effects, both of which were abrogated by the PI3K inhibitor alpelisib. Taken together, we describe a distinct and novel pathway of carcinogenesis in which tamoxifen acts as a driver event in the uterus and promotes tumor development in a mutation-independent manner. Indeed, tamoxifen may increase the risk of UC by activating the PI3K pathway, which can substitute for the early acquisition of oncogenic PIK3CA or PIK3R1 mutations observed in non–TA-UC tumors. Furthermore, the ability of a PI3K inhibitor to reduce cell proliferation in our mouse model raises the possibility that downregulating the PI3K pathway may prevent or significantly reduce TA-UC development, offering a potential future therapeutic and prevention strategy for specific high-risk patients undergoing tamoxifen therapy. Citation Format: Kirsten Kubler, Agostina Nardone, Shankara Anand, Daniel Gorvich, Marjolein Droog, Francisco Hermida-Prado, Tara Akshi, Avery S Feit, Gabriella Cohen, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, William J Gibson, Cloud P Paweletz, Eliezer M Van Allen, Flora E van Leeuwen, Petra Nederlof, Harry Hollema, Quang-Dé Nguyen, Marian JE Mourits, Ignaty Leshchiner, Chip Stewart, Ursula A Matulonis, Wilbert Zwart, Yosef E Maruvka, Gad Getz, Rinath Jeselsohn. Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-09.
Published: 2022
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25. Supplementary Figures S1-S11 from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing

Author: Benjamin L. Ebert, Siddhartha Jaiswal, Robert K. Bradley, Gad Getz, Chip Stewart, Elli Papaemmanuil, Luca Malcovati, Eva Hellstrom-Lindberg, Steven A. Carr, Kasper Lage, Donna S. Neuberg, Monkol Lek, Daniel G. MacArthur, Ruth Loos, Andrew D. Johnson, Michael H. Cho, Pinkal Desai, Bruce M. Psaty, Shankara Anand, Alex Barbera, Timothy Wood, Amaro Taylor-Weiner, Andrew Dunford, Abhishek Niroula, Mendy Miller, Joshua S. Weinstock, Alexander G. Bick, Björn Nilsson, Edyta Malolepsza, Benjamin Tanenbaum, Caroline Stanclift, Monica Schenone, Waihay Wong, Akansha Tarun, Marie McConkey, Cecilia A. Castellano, Anna Gallì, Maria Creignou, Gabriele Todisco, Emma R. Hoppe, Elsa Bernard, Matthew Leventhal, and Ellen M. Beauchamp
Abstract: Supplementary Figures S1-S11
Published: 2023
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26. Supplementary Tables S1-S19 from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing

Author: Benjamin L. Ebert, Siddhartha Jaiswal, Robert K. Bradley, Gad Getz, Chip Stewart, Elli Papaemmanuil, Luca Malcovati, Eva Hellstrom-Lindberg, Steven A. Carr, Kasper Lage, Donna S. Neuberg, Monkol Lek, Daniel G. MacArthur, Ruth Loos, Andrew D. Johnson, Michael H. Cho, Pinkal Desai, Bruce M. Psaty, Shankara Anand, Alex Barbera, Timothy Wood, Amaro Taylor-Weiner, Andrew Dunford, Abhishek Niroula, Mendy Miller, Joshua S. Weinstock, Alexander G. Bick, Björn Nilsson, Edyta Malolepsza, Benjamin Tanenbaum, Caroline Stanclift, Monica Schenone, Waihay Wong, Akansha Tarun, Marie McConkey, Cecilia A. Castellano, Anna Gallì, Maria Creignou, Gabriele Todisco, Emma R. Hoppe, Elsa Bernard, Matthew Leventhal, and Ellen M. Beauchamp
Abstract: Supplementary Tables S1-S19
Published: 2023
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27. Data from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing

Author: Benjamin L. Ebert, Siddhartha Jaiswal, Robert K. Bradley, Gad Getz, Chip Stewart, Elli Papaemmanuil, Luca Malcovati, Eva Hellstrom-Lindberg, Steven A. Carr, Kasper Lage, Donna S. Neuberg, Monkol Lek, Daniel G. MacArthur, Ruth Loos, Andrew D. Johnson, Michael H. Cho, Pinkal Desai, Bruce M. Psaty, Shankara Anand, Alex Barbera, Timothy Wood, Amaro Taylor-Weiner, Andrew Dunford, Abhishek Niroula, Mendy Miller, Joshua S. Weinstock, Alexander G. Bick, Björn Nilsson, Edyta Malolepsza, Benjamin Tanenbaum, Caroline Stanclift, Monica Schenone, Waihay Wong, Akansha Tarun, Marie McConkey, Cecilia A. Castellano, Anna Gallì, Maria Creignou, Gabriele Todisco, Emma R. Hoppe, Elsa Bernard, Matthew Leventhal, and Ellen M. Beauchamp
Abstract: Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader ZBTB33 as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in patients with myelodysplastic syndrome. Zbtb33-edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and myelodysplastic syndromes.Significance:Mutations in known driver genes can be found in only about half of individuals with clonal hematopoiesis. Here, we performed a somatic mutation discovery effort in nonmalignant blood samples, which identified novel candidate genes that may play biological roles in hematopoietic stem cell expansion and hematologic malignancies.This article is highlighted in the In This Issue feature, p. 403
Published: 2023
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28. Supplementary Figures and Tables from MinimuMM-seq: Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

Author: Irene M. Ghobrial, Gad Getz, Daniel Auclair, Chip Stewart, Patricia T. Greipp, Omar Nadeem, Richard G. Del Mastro, Frank K. Kuhr, Ziao Lin, Amanda Cao, Jacqueline Perry, Jenna B. Beckwith, Laura Hevenor, Hadley Barr, Erica M. Horowitz, Nang Kham Su, Annie N. Cowan, Tarek H. Mouhieddine, Romanos Sklavenitis-Pistofidis, Andrew Dunford, Cody J. Boehner, Elizabeth D. Lightbody, Jean-Baptiste Alberge, and Ankit K. Dutta
Abstract: Supplementary data contains additional Materials and Methods used to generate results presented only in the supplementary figures and tables, as well as more detailed bioinformatics methods. Figure S1 shows correlation between clinical measures of disease pathology, survival, and circulating tumor cells enumeration. Figure S2 shows characteristics of isolated circulating tumor cells from peripheral blood of precursor disease patients. Figure S3 shows cohort-level genomic characterization of tumor in MM precursor stages with CTCs. Figure S4 shows longitudinal and tissue-matched genomic characterization of driver mutations. Figure S5 shows comparison of mutational processes between BMPCs and CTCs assigned to most likely PCAWG composite reference signature. Table S1 shows clinical characteristics and sampling of participants in this study. Table S2 shows whole-genome sequencing coverage and library metrics. Table S3 shows clinical BM FISH results and cells recovered for cohort with matched samples. Table S4 shows comparison of BCR sequence between BMPCs and CTCs. Table S5 shows clinical BM FISH results of peripheral blood only cohort and CTCs recovered. Table S6 shows enumeration of single nucleotide variants and short insertions and deletions discovered from WGS of CTCs. Table S7 shows enumeration of structural variants reconstructed from WGS of CTCs.
Published: 2023
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29. Data from MinimuMM-seq: Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

Author: Irene M. Ghobrial, Gad Getz, Daniel Auclair, Chip Stewart, Patricia T. Greipp, Omar Nadeem, Richard G. Del Mastro, Frank K. Kuhr, Ziao Lin, Amanda Cao, Jacqueline Perry, Jenna B. Beckwith, Laura Hevenor, Hadley Barr, Erica M. Horowitz, Nang Kham Su, Annie N. Cowan, Tarek H. Mouhieddine, Romanos Sklavenitis-Pistofidis, Andrew Dunford, Cody J. Boehner, Elizabeth D. Lightbody, Jean-Baptiste Alberge, and Ankit K. Dutta
Abstract: Multiple myeloma (MM) develops from well-defined precursor stages; however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. We enumerated circulating tumor cells (CTC) from 261 patients (84 monoclonal gammopathy of undetermined significance, 155 smoldering multiple myeloma, and 22 MM), with neoplastic cells detected in 84%. We developed a novel approach, MinimuMM-seq, which enables the detection of translocations and copy-number abnormalities through whole-genome sequencing of highly pure CTCs. Application to CTCs in a cohort of 51 patients, 24 with paired BM, was able to detect 100% of clinically reported BM biopsy events and could replace molecular cytogenetics for diagnostic yield and risk classification. Longitudinal sampling of CTCs in 8 patients revealed major clones could be tracked in the blood, with clonal evolution and shifting dynamics of subclones over time. Our findings provide proof of concept that CTC detection and genomic profiling could be used clinically for monitoring and managing disease in MM.Significance:In this study, we established an approach enabling the enumeration and sequencing of CTCs to replace standard molecular cytogenetics. CTCs harbored the same pathognomonic MM abnormalities as BM plasma cells. Longitudinal sampling of serial CTCs was able to track clonal dynamics over time and detect the emergence of high-risk genetic subclones.This article is highlighted in the In This Issue feature, p. 247
Published: 2023
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30. Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.Significance:Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494
Published: 2023
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31. Table S3 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Table S3 contains the karyotypes of 16 genome-wide LOH MPM cases from the BWH cohort.
Published: 2023
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32. Supplementary Table S16 from The Genomic Landscape of Pediatric Ewing Sarcoma

Author: Kimberly Stegmaier, Jaume Mora, Gad Getz, Todd R. Golub, Mark D. Fleming, Carlos Rodriguez-Galindo, Miguel N. Rivera, Angela Schwarz-Cruz y Celis, Ivan Imaz-Rosshandler, Matthew DeFelice, Brendan Blumenstiel, Sara Seepo, Daniel Auclair, Lauren Ambrogio, Mara Rosenberg, Petar Stojanov, Michael S. Lawrence, Kristian Cibulskis, Andrey Sivachenko, Aaron McKenna, Mariona Suñol, Cinzia Lavarino, Carmen de Torres, Aaron R. Thorner, Swapnil S. Mehta, Sachet A. Shukla, Scott L. Carter, Adam Kiezun, Monica L. Calicchio, Kyle C. Kurek, Gabriela Alexe, Amaro Taylor-Weiner, Chip Stewart, and Brian D. Crompton
Abstract: Variants identified from WES of 11 cell lines after filtering.
Published: 2023
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33. Supplementary Methods, Figure Legends, Figures S1 - S6, Tables S1, S3 - S6, S8 - S15, S17 from The Genomic Landscape of Pediatric Ewing Sarcoma

Author: Kimberly Stegmaier, Jaume Mora, Gad Getz, Todd R. Golub, Mark D. Fleming, Carlos Rodriguez-Galindo, Miguel N. Rivera, Angela Schwarz-Cruz y Celis, Ivan Imaz-Rosshandler, Matthew DeFelice, Brendan Blumenstiel, Sara Seepo, Daniel Auclair, Lauren Ambrogio, Mara Rosenberg, Petar Stojanov, Michael S. Lawrence, Kristian Cibulskis, Andrey Sivachenko, Aaron McKenna, Mariona Suñol, Cinzia Lavarino, Carmen de Torres, Aaron R. Thorner, Swapnil S. Mehta, Sachet A. Shukla, Scott L. Carter, Adam Kiezun, Monica L. Calicchio, Kyle C. Kurek, Gabriela Alexe, Amaro Taylor-Weiner, Chip Stewart, and Brian D. Crompton
Abstract: This file contains supplementary methods, supplementary references, supplementary figures S1-S6, supplementary tables S1, S3-S6, S8-S15, and S17, and legends for all supplementary figures and tables. Supplementary Figure S1. Summary of Ewing sarcoma tumor and cell line cohorts. Supplementary Figure S2. RNASeq validation of mutations identified by WES and WGS. Supplementary Figure S3. Power calculations for the detection of significantly mutated genes. Supplementary Figure S4. Copy number variants in Ewing sarcoma tumors. Supplementary Figure S5. ETS1 deletions associated with EWS/FLI rearrangements. Supplementary Figure S6. Copy number variants in diagnostic vs. treated Ewing sarcoma tumors. Supplementary Figure S7. SCNAs in paired Ewing sarcoma tumor samples. Supplementary Table S1. Tissue samples. Supplementary Table S3. Multiply mutated genes. Supplementary Table S4. Rearrangements and fusions detected by WGS and RNASeq. Supplementary Table S5. Mutational significance for tumor/normal pairs. Supplementary Table S6. Rate of coding mutations in Ewing sarcoma tumors. Supplementary Table S8. Mutational significance for all tumors. Supplementary Table S9. Gene set enrichment analyses of mutated genes. Supplementary Table S10. Significance of arm-level SCNAs. Supplementary Table S11. Multiply mutated genes of interest in all sample cohorts. Supplementary Table S12. Immunohistochemical staining of STAG2 in Ewing sarcoma tumors. Supplementary Table S13. Gene set enrichment analyses of STAG2 expressing vs. STAG2 loss. Supplementary Table S14. Gene and gene-fragment RPKM Values for EWS and ETS genes. Supplementary Table S15. ETS1 copy-number changes. Supplementary Table S17. Gene set enrichment analyses of tumors vs. cell lines.
Published: 2023
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34. Supplementary Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Supplementary materials and methods, as well as supplementary figures S1-S7.
Published: 2023
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35. Data from The Genomic Landscape of Pediatric Ewing Sarcoma

Author: Kimberly Stegmaier, Jaume Mora, Gad Getz, Todd R. Golub, Mark D. Fleming, Carlos Rodriguez-Galindo, Miguel N. Rivera, Angela Schwarz-Cruz y Celis, Ivan Imaz-Rosshandler, Matthew DeFelice, Brendan Blumenstiel, Sara Seepo, Daniel Auclair, Lauren Ambrogio, Mara Rosenberg, Petar Stojanov, Michael S. Lawrence, Kristian Cibulskis, Andrey Sivachenko, Aaron McKenna, Mariona Suñol, Cinzia Lavarino, Carmen de Torres, Aaron R. Thorner, Swapnil S. Mehta, Sachet A. Shukla, Scott L. Carter, Adam Kiezun, Monica L. Calicchio, Kyle C. Kurek, Gabriela Alexe, Amaro Taylor-Weiner, Chip Stewart, and Brian D. Crompton
Abstract: Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. In this study, we describe the somatic landscape of pediatric Ewing sarcoma. These tumors are among the most genetically normal cancers characterized to date, with only EWS–ETS rearrangements identified in the majority of tumors. STAG2 loss, however, is present in more than 15% of Ewing sarcoma tumors; occurs by point mutation, rearrangement, and likely nongenetic mechanisms; and is associated with disease dissemination. Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways, highlighting the need for new therapeutic approaches to target EWS–ETS fusions in this disease.Significance: We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS–ETS fusions. We found remarkably few mutations. However, we discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing sarcoma. Cancer Discov; 4(11); 1326–41. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 1243
Published: 2023
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36. Supplemental Figure 1 from Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer

Author: Rinath Jeselsohn, Gad Getz, Chip Stewart, Eric P. Winer, Ian E. Krop, Donald P. McDonnell, Nadine Tung, Sara M. Tolaney, Nabihah Tayob, Ignaty Leshchiner, Carrie Cibulskis, Niall J. Lennon, Candace Patterson, Agostina Nardone, Rebecca Rees, Leilani Anderson, Douglas Russo, Tim Coorens, Albert Grinshpun, Tianyu Li, and Junko Tsuji
Abstract: Supplemental Figure 1: Consort diagram
Published: 2023
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37. Supplementary Data from Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer

Author: Rinath Jeselsohn, Gad Getz, Chip Stewart, Eric P. Winer, Ian E. Krop, Donald P. McDonnell, Nadine Tung, Sara M. Tolaney, Nabihah Tayob, Ignaty Leshchiner, Carrie Cibulskis, Niall J. Lennon, Candace Patterson, Agostina Nardone, Rebecca Rees, Leilani Anderson, Douglas Russo, Tim Coorens, Albert Grinshpun, Tianyu Li, and Junko Tsuji
Abstract: Supplementary tables 1-4 and supplementary figure legend
Published: 2023
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38. Supplemental Figure 5 from Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer

Author: Rinath Jeselsohn, Gad Getz, Chip Stewart, Eric P. Winer, Ian E. Krop, Donald P. McDonnell, Nadine Tung, Sara M. Tolaney, Nabihah Tayob, Ignaty Leshchiner, Carrie Cibulskis, Niall J. Lennon, Candace Patterson, Agostina Nardone, Rebecca Rees, Leilani Anderson, Douglas Russo, Tim Coorens, Albert Grinshpun, Tianyu Li, and Junko Tsuji
Abstract: Supplemental Figure 5: SSNVs detected in the cancer-related genes across 68 ctDNA WES samples
Published: 2023
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39. Supplemental Figure 2 from Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer

Author: Rinath Jeselsohn, Gad Getz, Chip Stewart, Eric P. Winer, Ian E. Krop, Donald P. McDonnell, Nadine Tung, Sara M. Tolaney, Nabihah Tayob, Ignaty Leshchiner, Carrie Cibulskis, Niall J. Lennon, Candace Patterson, Agostina Nardone, Rebecca Rees, Leilani Anderson, Douglas Russo, Tim Coorens, Albert Grinshpun, Tianyu Li, and Junko Tsuji
Abstract: Supplemental Figure 2: Plasma circulating tumor DNA (ctDNA) collection and analysis
Published: 2023
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40. Data from Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer

Author: Rinath Jeselsohn, Gad Getz, Chip Stewart, Eric P. Winer, Ian E. Krop, Donald P. McDonnell, Nadine Tung, Sara M. Tolaney, Nabihah Tayob, Ignaty Leshchiner, Carrie Cibulskis, Niall J. Lennon, Candace Patterson, Agostina Nardone, Rebecca Rees, Leilani Anderson, Douglas Russo, Tim Coorens, Albert Grinshpun, Tianyu Li, and Junko Tsuji
Abstract: Purpose:Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated.Patients and Methods:We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2− advanced breast cancer who progressed on prior ET (N = 36; NCT02448771).Results:The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0–7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5–13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment.Conclusions:The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2− breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.
Published: 2023
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41. Supplemental Figure 4 from Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer

Author: Rinath Jeselsohn, Gad Getz, Chip Stewart, Eric P. Winer, Ian E. Krop, Donald P. McDonnell, Nadine Tung, Sara M. Tolaney, Nabihah Tayob, Ignaty Leshchiner, Carrie Cibulskis, Niall J. Lennon, Candace Patterson, Agostina Nardone, Rebecca Rees, Leilani Anderson, Douglas Russo, Tim Coorens, Albert Grinshpun, Tianyu Li, and Junko Tsuji
Abstract: Supplemental Figure 4: Overview of SSNVs in 68 ctDNA WES samples
Published: 2023
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42. Supplemental Figure 6 from Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer

Author: Rinath Jeselsohn, Gad Getz, Chip Stewart, Eric P. Winer, Ian E. Krop, Donald P. McDonnell, Nadine Tung, Sara M. Tolaney, Nabihah Tayob, Ignaty Leshchiner, Carrie Cibulskis, Niall J. Lennon, Candace Patterson, Agostina Nardone, Rebecca Rees, Leilani Anderson, Douglas Russo, Tim Coorens, Albert Grinshpun, Tianyu Li, and Junko Tsuji
Abstract: Supplemental Figure 6: Evolutionary analysis of longitudinal plasma ctDNA samples
Published: 2023
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43. Table S4 from Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma

Author: Andrew J. Wagner, Eliezer M. Van Allen, Levi A. Garraway, Chandrajit P. Raut, George D. Demetri, Bradley Quade, Marisa R. Nucci, Jason L. Hornick, Gad Getz, Adam Tracy, Sara Seepo, Aaron Chevalier, Chip Stewart, Amaro Taylor-Weiner, Mara Rosenberg, Scott L. Carter, Stefano Sioletic, Suzanne George, and Ali Amin-Mansour
Abstract: Supplementary Table 4
Published: 2023
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44. Data from Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma

Author: Andrew J. Wagner, Eliezer M. Van Allen, Levi A. Garraway, Chandrajit P. Raut, George D. Demetri, Bradley Quade, Marisa R. Nucci, Jason L. Hornick, Gad Getz, Adam Tracy, Sara Seepo, Aaron Chevalier, Chip Stewart, Amaro Taylor-Weiner, Mara Rosenberg, Scott L. Carter, Stefano Sioletic, Suzanne George, and Ali Amin-Mansour
Abstract: Purpose:Leiomyosarcoma and liposarcoma are common subtypes of soft tissue sarcoma (STS). Patients with metastatic leiomyosarcoma or dedifferentiated liposarcoma (DDLPS) typically have worse outcomes compared with localized leiomyosarcoma or well-differentiated liposarcoma (WDLPS). A better understanding of genetic changes between primary/metastatic leiomyosarcoma and between WDLPS/DDLPS may provide insight into their genetic evolution.Experimental Design:We interrogated whole-exome sequencing (WES) from “trios” of normal tissue, primary tumor, and metastatic tumor from individual patients with leiomyosarcoma (n = 9), and trios of normal tissue, well-differentiated tumor, and dedifferentiated tumor from individual patients with liposarcoma (n = 19). Specifically, we performed mutational, copy number, and tumor evolution analyses on these cohorts and compared patterns among leiomyosarcoma and liposarcoma trios.Results:Leiomyosarcoma cases harbored shared drivers through a typical parent/child relationship where the metastatic tumor was derived from the primary tumor. In contrast, while all liposarcoma cases shared the characteristic focal chromosome 12 amplicon, most paired liposarcoma cases did not share additional mutations, suggesting a divergent evolutionary pattern from a common precursor. No highly recurrent genomic alterations from WES were identified that could be implicated as driving the progression of disease in either sarcoma subtype.Conclusions:From a genomic perspective, leiomyosarcoma metastases contain genetic alterations that are also found in primary tumors. WDLPS and DDLPS, however, appear to divergently evolve from a common precursor harboring 12q amplification, rather than as a transformation to a higher-grade tumor. Further efforts to identify specific drivers of these distinct evolutionary patterns may inform future translational and clinical research in STS.
Published: 2023
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45. Tables S11-S12 from Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma

Author: Andrew J. Wagner, Eliezer M. Van Allen, Levi A. Garraway, Chandrajit P. Raut, George D. Demetri, Bradley Quade, Marisa R. Nucci, Jason L. Hornick, Gad Getz, Adam Tracy, Sara Seepo, Aaron Chevalier, Chip Stewart, Amaro Taylor-Weiner, Mara Rosenberg, Scott L. Carter, Stefano Sioletic, Suzanne George, and Ali Amin-Mansour
Abstract: Supplementary Tables 11-12
Published: 2023
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46. Molecular map of chronic lymphocytic leukemia and its impact on outcome

Author: Binyamin A. Knisbacher, Ziao Lin, Cynthia K. Hahn, Ferran Nadeu, Martí Duran-Ferrer, Kristen E. Stevenson, Eugen Tausch, Julio Delgado, Alex Barbera-Mourelle, Amaro Taylor-Weiner, Pablo Bousquets-Muñoz, Ander Diaz-Navarro, Andrew Dunford, Shankara Anand, Helene Kretzmer, Jesus Gutierrez-Abril, Sara López-Tamargo, Stacey M. Fernandes, Clare Sun, Mariela Sivina, Laura Z. Rassenti, Christof Schneider, Shuqiang Li, Laxmi Parida, Alexander Meissner, François Aguet, Jan A. Burger, Adrian Wiestner, Thomas J. Kipps, Jennifer R. Brown, Michael Hallek, Chip Stewart, Donna S. Neuberg, José I. Martín-Subero, Xose S. Puente, Stephan Stilgenbauer, Catherine J. Wu, Elias Campo, and Gad Getz
Subjects: Leukemia, Lymphoma, Human Genome, B-Cell, Immunoglobulin Variable Region, Hematology, Genomics, Biological Sciences, Prognosis, Medical and Health Sciences, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic, Article, Rare Diseases, Clinical Research, Mutation, Genetics, Humans, Chronic, Cancer, Biotechnology, Developmental Biology
Abstract: Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history which is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy chain variable region of immunoglobulin genes (IGHV). To build the ‘CLL map,’ we integrated genomic, transcriptomic, and epigenomic data from 1148 patients. We identified 202 candidate genetic drivers of CLL (109 novel) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic, and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.
Published: 2022

47. Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident

Author: Yuri Belayev, Victor Kryuchkov, Leandro M. Colli, Amy Berrington de Gonzalez, Maureen Hatch, Yosi Maruvka, Meredith Yeager, Chase W. Nelson, Mingyi Wang, Ivan Golovanov, Casey L. Dagnall, Bari J. Ballew, Vibha Vij, Nori Nakamura, Iryna Illienko, Paul S. Albert, Mark P. Little, Weiyin Zhou, Kiyohiko Mabuchi, Elena Bakhanova, Natalia Gudzenko, Shalabh Suman, Clara Bodelon, Vadim V. Chumak, Gad Getz, Stephen J. Chanock, Cameron D. Palmer, Chip Stewart, Lisa Mirabello, Neal D. Freedman, Vladimir Drozdovitch, Mitchell J. Machiela, Dimitry Bazyka, David Belyi, Prachi Kothiyal, Michael Dean, Elizabeth K. Cahoon, and Amy Hutchinson
Subjects: Radiation exposure, Multidisciplinary, Transgenerational epigenetics, business.industry, Medicine, Physiology, Chernobyl Nuclear Accident, business, Article, De novo mutations, Ionizing radiation
Abstract: Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science , this issue p. eabg2538 , p. 725
Published: 2021
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48. Monitoring Plasma Cells and Clonal Emergence through Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma

Author: Ankit K. Dutta, Jean-Baptiste Alberge, Elizabeth D. Lightbody, Cody J. Boehner, Romanos Sklavenitis-Pistofidis, Amanda Cao, Tarek H. Mouhieddine, Anna Cowan, Nang Kham Su, Andrew Dunford, Erica Horowitz, Hadley Barr, Jenna B. Beckwith, Laura Hevenor, Jacqueline Perry, Ornkleaw Zepp, Thai Bui, Steven Gross, Omar Nadeem, Chip Stewart, Daniel Auclair, Gad Getz, and Irene Ghobrial
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022
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49. Reconstructing the Genomic History of Multiple Myeloma Precursor Disease: Novel Insights and Clinical Applicability

Author: Jean-Baptiste Alberge, Ankit K. Dutta, Elizabeth D. Lightbody, Andrea Poletti, Andrew Dunford, Oliver Priebe, Julian M. Hess, Cody J. Boehner, Romanos Sklavenitis-Pistofidis, Nang Kham Su, Erica Horowitz, Hadley Barr, Jenna B. Beckwith, Laura Hevenor, Katherine Towle, Jacqueline Perry, Esther Rheinbay, Chip Stewart, Gad Getz, and Irene Ghobrial
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022
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50. Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression

Author: Justin Cha, Cody J. Boehner, Nikhil C. Munshi, Romanos Sklavenitis-Pistofidis, Kwee Yong, Chip Stewart, Karma Salem, Eliezer M. Van Allen, Jihye Park, Yu-Tzu Tai, Andrew Dunford, Shankara Anand, Lorenzo Trippa, Amaro Taylor-Weiner, Jacob P. Laubach, Mark Bustoros, Benny Zhitomirsky, Robert A. Redd, Selina J Chavda, Irene M. Ghobrial, Shaji Kumar, Paul G. Richardson, Kenneth C. Anderson, François Aguet, Tarek H. Mouhieddine, P. Leif Bergsagel, Gad Getz, Mahshid Rahmat, Tineke Casneuf, Meletios A. Dimopoulos, Liudmila Elagina, Carl Jannes Neuse, Salomon Manier, Elizabeth A. Morgan, Ignaty Leshchiner, and Efstathis Kastritis
Subjects: Adult, Male, Smoldering Multiple Myeloma, Oncology, Cancer Research, medicine.medical_specialty, Genomic profiling, MEDLINE, 03 medical and health sciences, 0302 clinical medicine, Text mining, Risk Factors, Internal medicine, medicine, Humans, Prognostic models, Multiple myeloma, Aged, Aged, 80 and over, business.industry, Extramural, Disease progression, High-Throughput Nucleotide Sequencing, ORIGINAL REPORTS, Genomics, Middle Aged, medicine.disease, 030220 oncology & carcinogenesis, Risk stratification, Disease Progression, Female, Multiple Myeloma, business, 030215 immunology
Abstract: PURPOSE Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.
Published: 2020
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