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Levi A. Garraway

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https://www.readbyqxmd.com/read/29763622/a-convergence-based-framework-for-cancer-drug-resistance
#1
REVIEW
David J Konieczkowski, Cory M Johannessen, Levi A Garraway
Despite advances in cancer biology and therapeutics, drug resistance remains problematic. Resistance is often multifactorial, heterogeneous, and prone to undersampling. Nonetheless, many individual mechanisms of targeted therapy resistance may coalesce into a smaller number of convergences, including pathway reactivation (downstream re-engagement of original effectors), pathway bypass (recruitment of a parallel pathway converging on the same downstream output), and pathway indifference (development of a cellular state independent of the initial therapeutic target)...
May 14, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29656892/cancer-germline-antigen-expression-discriminates-clinical-outcome-to-ctla-4-blockade
#2
Sachet A Shukla, Pavan Bachireddy, Bastian Schilling, Christina Galonska, Qian Zhan, Clyde Bango, Rupert Langer, Patrick C Lee, Daniel Gusenleitner, Derin B Keskin, Mehrtash Babadi, Arman Mohammad, Andreas Gnirke, Kendell Clement, Zachary J Cartun, Eliezer M Van Allen, Diana Miao, Ying Huang, Alexandra Snyder, Taha Merghoub, Jedd D Wolchok, Levi A Garraway, Alexander Meissner, Jeffrey S Weber, Nir Hacohen, Donna Neuberg, Patrick R Potts, George F Murphy, Christine G Lian, Dirk Schadendorf, F Stephen Hodi, Catherine J Wu
CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro...
April 6, 2018: Cell
https://www.readbyqxmd.com/read/29628419/increased-tumor-glycolysis-characterizes-immune-resistance-to-adoptive-t-cell-therapy
#3
Tina Cascone, Jodi A McKenzie, Rina M Mbofung, Simone Punt, Zhe Wang, Chunyu Xu, Leila J Williams, Zhiqiang Wang, Christopher A Bristow, Alessandro Carugo, Michael D Peoples, Lerong Li, Tatiana Karpinets, Lu Huang, Shruti Malu, Caitlin Creasy, Sara E Leahey, Jiong Chen, Yuan Chen, Helen Pelicano, Chantale Bernatchez, Y N Vashisht Gopal, Timothy P Heffernan, Jianhua Hu, Jing Wang, Rodabe N Amaria, Levi A Garraway, Peng Huang, Peiying Yang, Ignacio I Wistuba, Scott E Woodman, Jason Roszik, R Eric Davis, Michael A Davies, John V Heymach, Patrick Hwu, Weiyi Peng
Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis-related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo...
March 17, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29610475/the-long-tail-of-oncogenic-drivers-in-prostate-cancer
#4
Joshua Armenia, Stephanie A M Wankowicz, David Liu, Jianjiong Gao, Ritika Kundra, Ed Reznik, Walid K Chatila, Debyani Chakravarty, G Celine Han, Ilsa Coleman, Bruce Montgomery, Colin Pritchard, Colm Morrissey, Christopher E Barbieri, Himisha Beltran, Andrea Sboner, Zafeiris Zafeiriou, Susana Miranda, Craig M Bielski, Alexander V Penson, Charlotte Tolonen, Franklin W Huang, Dan Robinson, Yi Mi Wu, Robert Lonigro, Levi A Garraway, Francesca Demichelis, Philip W Kantoff, Mary-Ellen Taplin, Wassim Abida, Barry S Taylor, Howard I Scher, Peter S Nelson, Johann S de Bono, Mark A Rubin, Charles L Sawyers, Arul M Chinnaiyan, Nikolaus Schultz, Eliezer M Van Allen
Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway...
April 2, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29510987/genetic-mechanisms-of-immune-evasion-in-colorectal-cancer
#5
Catherine S Grasso, Marios Giannakis, Daniel K Wells, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Michael Quist, Jonathan A Nowak, Reiko Nishihara, Zhi Rong Qian, Kentaro Inamura, Teppei Morikawa, Katsuhiko Nosho, Gabriel Abril-Rodriguez, Charles Connolly, Helena Escuin-Ordinas, Milan S Geybels, William M Grady, Li Hsu, Siwen Hu-Lieskovan, Jeroen R Huyghe, Yeon Joo Kim, Paige Krystofinski, Mark D M Leiserson, Dennis J Montoya, Brian B Nadel, Matteo Pellegrini, Colin C Pritchard, Cristina Puig-Saus, Elleanor H Quist, Ben J Raphael, Stephen J Salipante, Daniel Sanghoon Shin, Eve Shinbrot, Brian Shirts, Sachet Shukla, Janet L Stanford, Wei Sun, Jennifer Tsoi, Alexander Upfill-Brown, David A Wheeler, Catherine J Wu, Ming Yu, Syed H Zaidi, Jesse M Zaretsky, Stacey B Gabriel, Eric S Lander, Levi A Garraway, Thomas J Hudson, Charles S Fuchs, Antoni Ribas, Shuji Ogino, Ulrike Peters
To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity...
March 6, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29478780/inherited-dna-repair-defects-in-colorectal-cancer
#6
Saud H AlDubayan, Marios Giannakis, Nathanael D Moore, G Celine Han, Brendan Reardon, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Reiko Nishihara, Zhirong Qian, Li Liu, Matthew B Yurgelun, Sapna Syngal, Levi A Garraway, Shuji Ogino, Charles S Fuchs, Eliezer M Van Allen
Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC...
March 1, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29259186/mutational-patterns-in-chemotherapy-resistant-muscle-invasive-bladder-cancer
#7
David Liu, Philip Abbosh, Daniel Keliher, Brendan Reardon, Diana Miao, Kent Mouw, Amaro Weiner-Taylor, Stephanie Wankowicz, Garam Han, Min Yuen Teo, Catharine Cipolla, Jaegil Kim, Gopa Iyer, Hikmat Al-Ahmadie, Essel Dulaimi, David Y T Chen, R Katherine Alpaugh, Jean Hoffman-Censits, Levi A Garraway, Gad Getz, Scott L Carter, Joaquim Bellmunt, Elizabeth R Plimack, Jonathan E Rosenberg, Eliezer M Van Allen
Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity...
December 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29208398/future-cancer-research-priorities-in-the-usa-a-lancet-oncology-commission
#8
REVIEW
Elizabeth M Jaffee, Chi Van Dang, David B Agus, Brian M Alexander, Kenneth C Anderson, Alan Ashworth, Anna D Barker, Roshan Bastani, Sangeeta Bhatia, Jeffrey A Bluestone, Otis Brawley, Atul J Butte, Daniel G Coit, Nancy E Davidson, Mark Davis, Ronald A DePinho, Robert B Diasio, Giulio Draetta, A Lindsay Frazier, Andrew Futreal, Sam S Gambhir, Patricia A Ganz, Levi Garraway, Stanton Gerson, Sumit Gupta, James Heath, Ruth I Hoffman, Cliff Hudis, Chanita Hughes-Halbert, Ramy Ibrahim, Hossein Jadvar, Brian Kavanagh, Rick Kittles, Quynh-Thu Le, Scott M Lippman, David Mankoff, Elaine R Mardis, Deborah K Mayer, Kelly McMasters, Neal J Meropol, Beverly Mitchell, Peter Naredi, Dean Ornish, Timothy M Pawlik, Jeffrey Peppercorn, Martin G Pomper, Derek Raghavan, Christine Ritchie, Sally W Schwarz, Richard Sullivan, Richard Wahl, Jedd D Wolchok, Sandra L Wong, Alfred Yung
We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment...
November 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29144510/characterizing-reduced-coverage-regions-through-comparison-of-exome-and-genome-sequencing-data-across-10-centers
#9
Rashesh V Sanghvi, Christian J Buhay, Bradford C Powell, Ellen A Tsai, Michael O Dorschner, Celine S Hong, Matthew S Lebo, Ariella Sasson, David S Hanna, Sean McGee, Kevin M Bowling, Gregory M Cooper, David E Gray, Robert J Lonigro, Andrew Dunford, Christine A Brennan, Carrie Cibulskis, Kimberly Walker, Mauricio O Carneiro, Joshua Sailsbery, Lucia A Hindorff, Dan R Robinson, Avni Santani, Mahdi Sarmady, Heidi L Rehm, Leslie G Biesecker, Deborah A Nickerson, Carolyn M Hutter, Levi Garraway, Donna M Muzny, Nikhil Wagle
PurposeAs massively parallel sequencing is increasingly being used for clinical decision making, it has become critical to understand parameters that affect sequencing quality and to establish methods for measuring and reporting clinical sequencing standards. In this report, we propose a definition for reduced coverage regions and describe a set of standards for variant calling in clinical sequencing applications.MethodsTo enable sequencing centers to assess the regions of poor sequencing quality in their own data, we optimized and used a tool (ExCID) to identify reduced coverage loci within genes or regions of particular interest...
November 16, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29109393/scalable-whole-exome-sequencing-of-cell-free-dna-reveals-high-concordance-with-metastatic-tumors
#10
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, Matthew Meyerson
Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing...
November 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29101162/-ex-vivo-profiling-of-pd-1-blockade-using-organotypic-tumor-spheroids
#11
Russell W Jenkins, Amir R Aref, Patrick H Lizotte, Elena Ivanova, Susanna Stinson, Chensheng W Zhou, Michaela Bowden, Jiehui Deng, Hongye Liu, Diana Miao, Meng Xiao He, William Walker, Gao Zhang, Tian Tian, Chaoran Cheng, Zhi Wei, Sangeetha Palakurthi, Mark Bittinger, Hans Vitzthum, Jong Wook Kim, Ashley Merlino, Max Quinn, Chandrasekar Venkataramani, Joshua A Kaplan, Andrew Portell, Prafulla C Gokhale, Bart Phillips, Alicia Smart, Asaf Rotem, Robert E Jones, Lauren Keogh, Maria Anguiano, Lance Stapleton, Zhiheng Jia, Michal Barzily-Rokni, Israel Cañadas, Tran C Thai, Marc R Hammond, Raven Vlahos, Eric S Wang, Hua Zhang, Shuai Li, Glenn J Hanna, Wei Huang, Mai P Hoang, Adriano Piris, Jean-Pierre Eliane, Anat O Stemmer-Rachamimov, Lisa Cameron, Mei-Ju Su, Parin Shah, Benjamin Izar, Manisha Thakuria, Nicole R LeBoeuf, Guilherme Rabinowits, Viswanath Gunda, Sareh Parangi, James M Cleary, Brian C Miller, Shunsuke Kitajima, Rohit Thummalapalli, Benchun Miao, Thanh U Barbie, Vivek Sivathanu, Joshua Wong, William G Richards, Raphael Bueno, Charles H Yoon, Juan Miret, Meenhard Herlyn, Levi A Garraway, Eliezer M Van Allen, Gordon J Freeman, Paul T Kirschmeier, Jochen H Lorch, Patrick A Ott, F Stephen Hodi, Keith T Flaherty, Roger D Kamm, Genevieve M Boland, Kwok-Kin Wong, David Dornan, Cloud Peter Paweletz, David A Barbie
Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture...
February 2018: Cancer Discovery
https://www.readbyqxmd.com/read/28837809/decomposing-oncogenic-transcriptional-signatures-to-generate-maps-of-divergent-cellular-states
#12
Jong Wook Kim, Omar O Abudayyeh, Huwate Yeerna, Chen-Hsiang Yeang, Michelle Stewart, Russell W Jenkins, Shunsuke Kitajima, David J Konieczkowski, Kate Medetgul-Ernar, Taylor Cavazos, Clarence Mah, Stephanie Ting, Eliezer M Van Allen, Ofir Cohen, John Mcdermott, Emily Damato, Andrew J Aguirre, Jonathan Liang, Arthur Liberzon, Gabriella Alexe, John Doench, Mahmoud Ghandi, Francisca Vazquez, Barbara A Weir, Aviad Tsherniak, Aravind Subramanian, Karina Meneses-Cime, Jason Park, Paul Clemons, Levi A Garraway, David Thomas, Jesse S Boehm, David A Barbie, William C Hahn, Jill P Mesirov, Pablo Tamayo
The systematic sequencing of the cancer genome has led to the identification of numerous genetic alterations in cancer. However, a deeper understanding of the functional consequences of these alterations is necessary to guide appropriate therapeutic strategies. Here, we describe Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework to organize individual tumor samples with shared oncogenic alterations onto a reference map defined by their underlying cellular states. We applied the methodology to the RAS pathway and identified nine distinct components that reflect transcriptional activities downstream of RAS and defined several functional states associated with patterns of transcriptional component activation that associates with genomic hallmarks and response to genetic and pharmacological perturbations...
August 23, 2017: Cell Systems
https://www.readbyqxmd.com/read/28805821/opposing-effects-of-cancer-type-specific-spop-mutants-on-bet-protein-degradation-and-sensitivity-to-bet-inhibitors
#13
Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev, David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus, Peter Schraml, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr, Levi A Garraway, Peter J Wild, Jean-Philippe P Theurillat
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#14
Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28794284/genomic-profiling-of-er-breast-cancers-after-short-term-estrogen-suppression-reveals-alterations-associated-with-endocrine-resistance
#15
Jennifer M Giltnane, Katherine E Hutchinson, Thomas P Stricker, Luigi Formisano, Christian D Young, Monica V Estrada, Mellissa J Nixon, Liping Du, Violeta Sanchez, Paula Gonzalez Ericsson, Maria G Kuba, Melinda E Sanders, Xinmeng J Mu, Eliezer M Van Allen, Nikhil Wagle, Ingrid A Mayer, Vandana Abramson, Henry Gόmez, Monica Rizzo, Weiyi Toy, Sarat Chandarlapaty, Erica L Mayer, Jason Christiansen, Danielle Murphy, Kerry Fitzgerald, Kai Wang, Jeffrey S Ross, Vincent A Miller, Phillip J Stephens, Roman Yelensky, Levi Garraway, Yu Shyr, Ingrid Meszoely, Justin M Balko, Carlos L Arteaga
Inhibition of proliferation in estrogen receptor-positive (ER+ ) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER+ /human epidermal growth factor receptor 2-negative (HER2- ) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28757884/the-fuzzy-world-of-precision-medicine-deliberations-of-a-precision-medicine-tumor-board
#16
Sarah A McGraw, Judy Garber, Pasi A Jänne, Neal Lindeman, Nelly Oliver, Lynette M Sholl, Eliezer M Van Allen, Nikhil Wagle, Levi A Garraway, Steven Joffe, Stacy W Gray
AIM: To understand how a cancer precision medicine tumor board (CPM-TB) made choices about return of results. MATERIALS & METHODS: Observed CPM-TB deliberations and completed in-depth interviews with committee members. RESULTS: Responding to complex evidence of ambiguous significance, deliberations of the CPM-TB were predicated on analytic validity and clinical utility. Members had concerns both about potential harms due to returning results based on weak evidence and about withholding potentially meaningful results...
January 2017: Personalized Medicine
https://www.readbyqxmd.com/read/28753430/defining-a-cancer-dependency-map
#17
Aviad Tsherniak, Francisca Vazquez, Phil G Montgomery, Barbara A Weir, Gregory Kryukov, Glenn S Cowley, Stanley Gill, William F Harrington, Sasha Pantel, John M Krill-Burger, Robin M Meyers, Levi Ali, Amy Goodale, Yenarae Lee, Guozhi Jiang, Jessica Hsiao, William F J Gerath, Sara Howell, Erin Merkel, Mahmoud Ghandi, Levi A Garraway, David E Root, Todd R Golub, Jesse S Boehm, William C Hahn
Most human epithelial tumors harbor numerous alterations, making it difficult to predict which genes are required for tumor survival. To systematically identify cancer dependencies, we analyzed 501 genome-scale loss-of-function screens performed in diverse human cancer cell lines. We developed DEMETER, an analytical framework that segregates on- from off-target effects of RNAi. 769 genes were differentially required in subsets of these cell lines at a threshold of six SDs from the mean. We found predictive models for 426 dependencies (55%) by nonlinear regression modeling considering 66,646 molecular features...
July 27, 2017: Cell
https://www.readbyqxmd.com/read/28666115/ifn%C3%AE-dependent-tissue-immune-homeostasis-is-co-opted-in-the-tumor-microenvironment
#18
Christopher J Nirschl, Mayte Suárez-Fariñas, Benjamin Izar, Sanjay Prakadan, Ruth Dannenfelser, Itay Tirosh, Yong Liu, Qian Zhu, K Sanjana P Devi, Shaina L Carroll, David Chau, Melika Rezaee, Tae-Gyun Kim, Ruiqi Huang, Judilyn Fuentes-Duculan, George X Song-Zhao, Nicholas Gulati, Michelle A Lowes, Sandra L King, Francisco J Quintana, Young-Suk Lee, James G Krueger, Kavita Y Sarin, Charles H Yoon, Levi Garraway, Aviv Regev, Alex K Shalek, Olga Troyanskaya, Niroshana Anandasabapathy
Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28594900/systematic-genomic-and-translational-efficiency-studies-of-uveal-melanoma
#19
Chelsea Place Johnson, Ivana K Kim, Bita Esmaeli, Ali Amin-Mansour, Daniel J Treacy, Scott L Carter, Eran Hodis, Nikhil Wagle, Sara Seepo, Xiaoxing Yu, Anne Marie Lane, Evangelos S Gragoudas, Francisca Vazquez, Elizabeth Nickerson, Kristian Cibulskis, Aaron McKenna, Stacey B Gabriel, Gad Getz, Eliezer M Van Allen, Peter A C 't Hoen, Levi A Garraway, Scott E Woodman
To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays. Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells. We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX...
2017: PloS One
https://www.readbyqxmd.com/read/28515055/exome-sequencing-of-african-american-prostate-cancer-reveals-loss-of-function-erf-mutations
#20
Franklin W Huang, Juan Miguel Mosquera, Andrea Garofalo, Coyin Oh, Maria Baco, Ali Amin-Mansour, Bokang Rabasha, Samira Bahl, Stephanie A Mullane, Brian D Robinson, Saud Aldubayan, Francesca Khani, Beerinder Karir, Eejung Kim, Jeremy Chimene-Weiss, Matan Hofree, Alessandro Romanel, Joseph R Osborne, Jong Wook Kim, Gissou Azabdaftari, Anna Woloszynska-Read, Karen Sfanos, Angelo M De Marzo, Francesca Demichelis, Stacey Gabriel, Eliezer M Van Allen, Jill Mesirov, Pablo Tamayo, Mark A Rubin, Isaac J Powell, Levi A Garraway
African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing ( n = 102) and targeted validation ( n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF , an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3% to 5% of lethal castration-resistant prostate cancers...
September 2017: Cancer Discovery
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