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Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

NATURE GENETICS 2018年第10期50卷 1483-+页

作者： Reshef, Yakir A. Finucane, Hilary K. Kelley, David R. Gusev, Alexander Kotliar, Dylan Ulirsch, Jacob C. Hormozdiari, Farhad Nasser, Joseph O'Connor, Luke van de Geijn, Bryce Loh, Po-Ru Grossman, Sharon R. Bhatia, Gaurav Gazel, Steven Palamara, Pier Francesco Pinello, Luca Patterson, Nick Adams, Ryan P. Price, Alkes L. Harvard Univ Dept Comp Sci Cambridge MA 02138 USA Harvard MIT MD PhD Program Boston MA USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Calif Life Sci LLC San Francisco CA USA Dana Farber Canc Inst Boston MA 02115 USA Boston Childrens Hosp Boston MA USA Harvard TH Chan Sch Publ Hlth Dept Epidemiol Boston MA 02115 USA Harvard Univ Program Bioinformat & Integrat Genom Cambridge MA 02138 USA Brigham & Womens Hosp Dept Med Div Genet 75 Francis St Boston MA 02115 USA Harvard Med Sch Boston MA USA Univ Oxford Dept Stat Oxford England Massachusetts Gen Hosp Charlestown MA USA Harvard Med Sch Dept Pathol Boston MA USA Google Brain New York NY USA Princeton Univ Dept Comp Sci Princeton NJ 08544 USA Harvard TH Chan Sch Publ Hlth Dept Biostat Boston MA 02115 USA

Biological interpretation of genome-wide association study data frequently involves assessing whether SNPs linked to a biological process, for example, binding of a transcription factor, show unsigned enrichment for disease signal. However, signed annotations quantifying whether each SNP allele promotes or hinders the biological process can enable stronger statements about disease mechanism. We introduce a method, signed linkage disequilibrium profile regression, for detecting genome-wide directional effects of signed functional annotations on disease risk. We validate the method via simulations and application to molecular quantitative trait loci in blood, recovering known transcriptional regulators. We apply the method to expression quantitative trait loci in 48 Genotype-Tissue Expression tissues, identifying 651 transcription factor-tissue associations including 30 with robust evidence of tissue specificity. We apply the method to 46 diseases and complex traits (average n = 290 K), identifying 77 annotation-trait associations representing 12 independent transcription factor-trait associations, and characterize the underlying transcriptional programs using gene-set enrichment analyses. Our results implicate new causal disease genes and new disease mechanisms.

关键词： Epigenomics Gene regulation Genome-wide association studies

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Smoking and Risk of Colorectal Cancer Sub-classified by Tumor-infiltrating T Cells (vol 111, pg 42, 2019)

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JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 2019年第12期111卷 1365-1365页

作者： Hamada, Tsuyoshi Department of Oncologic Pathology Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MAProgram in Molecular Pathological Epidemiology Department of Pathology Department of Oncologic Pathology Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MADepartment of Nutrition Clinical and Translational Epidemiology Unit and Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MADepartment of NutritionDivision of Public Health Sciences Department of Surgery Washington University School of Medicine St. Louis MO Department of Oncologic Pathology Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MA Department of Oncologic Pathology Department of Oncologic PathologyDepartment of NutritionDivision of Public Health Sciences Department of Surgery Washington University School of Medicine St. Louis MODepartment of Epidemiology and Biostatistics and the Ministry of Education Key Lab of Environment and Health School of Public Health Huazhong University of Science and Technology Hubei P.R. China Department of Oncologic PathologyDepartment of Medical Oncology Chinese PLA General Hospital Beijing P.R. China Department of Oncologic Pathology Department of Oncologic PathologyCollege of Pharmacy Zhejiang Chinese Medical University Zhejiang P.R. China Department of Oncologic Pathology Department of Gastroenterology Rheumatology and Clinical Immunology Sapporo Medical University School of Medicine Sapporo Japan Department of NutritionDepartment of Food Science and Biotechnology Dongguk University Goyang the Republic of Korea Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MADepartment of

BackgroundEvidence indicates not only carcinogenic effect of cigarette smoking but also its immunosuppressive effect. We hypothesized that the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti-tumor adaptive immune *** follow-up of 134 981 participants (3 490 851 person-years) in the Nurses’ Health Study and Health Professionals Follow-up Study, we documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment. Using the duplication-method Cox regression model, we examined a differential association of smoking status with risk of colorectal carcinoma subclassified by densities of CD3⁺ cells, CD8⁺ cells, CD45RO (PTPRC)⁺ cells, or FOXP3⁺ cells. All statistical tests were *** association of smoking status with colorectal cancer risk differed by CD3⁺ cell density (P_{heterogeneity} = .007). Compared with never smokers, multivariable-adjusted hazard ratios for CD3⁺ cell-low colorectal cancer were 1.38 (95% confidence interval = 1.09 to 1.75) in former smokers and 1.59 (95% confidence interval = 1.14 to 2.23) in current smokers (P_trend = .002, across smoking status categories). In contrast, smoking status was not associated with CD3⁺ cell-high cancer risk (P_trend = .52). This differential association appeared consistent in strata of microsatellite instability, CpG island methylator phenotype, or BRAF mutation status. There was no statistically significant differential association according to densities of CD8⁺ cells, CD45RO⁺ cells, or FOXP3⁺ cells (P_{heterogeneity} > .04, with adjusted α of 0.01).ConclusionsColorectal cancer risk increased by smoking was stronger for tumors with lower T-lymphocyte response, suggesting an interplay of smoking and immunity in colorectal carcinogenesis.

关键词： Association (Psychology) cancer risk Smoking Colorectal Cancer Cancer of Colon Cigarette Smoking Immunosuppression (Physiology) Adaptive Immune Response Tumours T-Lymphocytes cigarette smoke

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Adversarial attacks against medical deep learning systems

arXiv

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arXiv 2018年

作者： Finlayson, Samuel G. Chung, Hyung Won Kohane, Isaac S. Beam, Andrew L. Department of Systems Biology and MD-PhD program Harvard Medical School MIT BostonMA Massachusetts Institute of Technology CambridgeMA United States Department of Biomedical Informatics Harvard Medical School BostonMA United States

The discovery of adversarial examples has raised concerns about the practical deployment of deep learning systems. In this paper, we demonstrate that adversarial examples are capable of manipulating deep learning systems across three clinical domains. For each of our representative medical deep learning classifiers, both white and black box attacks were highly successful. Our models are representative of the current state of the art in medical computer vision and, in some cases, directly reflect architectures already seeing deployment in real world clinical settings. In addition to the technical contribution of our paper, we synthesize a large body of knowledge about the healthcare system to argue that medicine may be uniquely susceptible to adversarial attacks, both in terms of monetary incentives and technical vulnerability. To this end, we outline the healthcare economy and the incentives it creates for fraud and provide concrete examples of how and why such attacks could be realistically carried out. We urge practitioners to be aware of current vulnerabilities when deploying deep learning systems in clinical settings, and encourage the machine learning community to further investigate the domain-specific characteristics of medical learning systems. Copyright © 2018, The Authors. All rights reserved.

关键词： Health care

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Field-deployable viral diagnostics using CRISPR-Cas13

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SCIENCE 2018年第6387期360卷 444-448页

作者： Myhrvold, Cameron Freije, Catherine A. Gootenberg, Jonathan S. Abudayyeh, Omar O. Metsky, Hayden C. Durbin, Ann F. Kellner, Max J. Tan, Amanda L. Paul, Lauren M. Parham, Leda A. Garcia, Kimberly F. Barnes, Kayla G. Chak, Bridget Mondini, Adriano Nogueira, Mauricio L. Isern, Sharon Michael, Scott F. Lorenzana, Ivette Yozwiak, Nathan L. MacInnis, Bronwyn L. Bosch, Irene Gehrke, Lee Zhang, Feng Sabeti, Pardis C. Broad Inst Massachusetts Inst Technol MIT & Harva Cambridge MA 02142 USA Harvard Univ Dept Organismal & Evolutionary Biol Ctr Syst Biol Cambridge MA 02138 USA Harvard Med Sch Div Med Sci PhD Program Virol Boston MA 02115 USA Harvard Med Sch Dept Syst Biol Boston MA 02115 USA MIT McGovern Inst Brain Res Cambridge MA 02139 USA MIT Dept Brain & Cognit Sci Cambridge MA 02139 USA MIT Dept Biol Engn Cambridge MA 02139 USA MIT Dept Hlth Sci & Technol Cambridge MA 02139 USA MIT Dept Elect Engn & Comp Sci Cambridge MA 02139 USA MIT Inst Med Engn & Sci Cambridge MA 02139 USA Florida Gulf Coast Univ Dept Biol Sci Ft Myers FL 33965 USA Univ Nacl Autonoma Honduras Inst Invest Microbiol Ctr Invest Genet Tegucigalpa Honduras Harvard Sch Publ Hlth Dept Immunol & Infect Dis Boston MA 02115 USA Sao Paulo State Univ Sch Pharmaceut Sci Araraquara Lab Publ Hlth Sao Paulo Brazil Fac Med Sao Jose do Rio Preto Lab Pesquisas Virol Sao Paulo Brazil Mt Sinai Sch Med Dept Med New York NY 10029 USA Harvard Med Sch Dept Microbiol & Immunobiol Boston MA 02115 USA HHMI Chevy Chase MD 20815 USA

mitigating global infectious disease requires diagnostic tools that are sensitive, specific, and rapidly field deployable. In this study, we demonstrate that the Cas13-based SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) platform can detect Zika virus (ZIKV) and dengue virus (DENV) in patient samples at concentrations as low as 1 copy per microliter. We developed HUDSON (heating unextracted diagnostic samples to obliterate nucleases), a protocol that pairs with SHERLOCK for viral detection directly from bodily fluids, enabling instrument-free DENVdetection directly from patient samples in <2 hours. We further demonstrate that SHERLOCK can distinguish the four DENV serotypes, as well as region-specific strains of ZIKV from the 2015-2016 pandemic. Finally, we report the rapid (<1 week) design and testing of instrument-free assays to detect clinically relevant viral single-nucleotide polymorphisms.

关键词： BIOTECHNOLOGY VIRAL disease diagnosis ZIKA virus infections DIAGNOSIS DENGUE DIAGNOSIS of fever COMMUNICABLE diseases ENZYMOLOGY

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Mapping a functional cancer genome atlas of tumor suppressors in mouse liver using AAV-CRISPR-mediated direct in vivo screening

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SCIENCE ADVANCES 2018年第2期4卷 5508-5508页

作者： Wang, Guangchuan Chow, Ryan D. Ye, Lupeng Guzman, Christopher D. Dai, Xiaoyun Dong, Matthew B. Zhang, Feng Sharp, Phillip A. Platt, Randall J. Chen, Sidi Yale Univ Sch Med Dept Genet New Haven CT 06510 USA Yale Univ Sch Med Syst Biol Inst 850 West Campus Dr West Haven CT 06516 USA Yale Univ Sch Med MD PhD Program New Haven CT 06510 USA Yale Univ Sch Med Immunobiol Program New Haven CT 06510 USA Yale Univ Dept Immunobiol Sch Med New Haven CT 06510 USA Broad Inst Massachusetts Inst Technol MIT 75 Ames St Cambridge MA 02142 USA Harvard Univ 75 Ames St Cambridge MA 02142 USA MIT Dept Biol Engn Cambridge MA 02142 USA MIT Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Biol Cambridge MA 02139 USA Swiss Fed Inst Technol Dept Biosyst Sci & Engn Mattenstr 26 CH-4058 Basel Switzerland Univ Basel Dept Chem Peterspl 1 CH-4003 Basel Switzerland Yale Univ Biol & Biomed Sci Program Sch Med West Haven CT 06516 USA Yale Univ Comprehens Canc Ctr Sch Med West Haven CT 06516 USA Yale Univ Stem Cell Ctr Sch Med West Haven CT 06516 USA

Cancer genomics consortia have charted the landscapes of numerous human cancers. Whereas somemutations were found in classical oncogenes and tumor suppressors, others have not yet been functionally studied in vivo. To date, a comprehensive assessment of how these genes influence oncogenesis is lacking. We performed direct high-throughput in vivo mapping of functional variants in an autochthonous mouse model of cancer. Using adeno-associated viruses (AAVs) carrying a single-guide RNA (sgRNA) library targeting putative tumor suppressor genes significantly mutated in human cancers, we directly pool-mutagenized the livers of Cre-inducible CRISPR (clustered regularly interspaced short palindromic repeats)-associated protein 9 (Cas9) mice. All mice that received the AAV-mTSG library developed liver cancer and died within 4 months. We used molecular inversion probe sequencing of the sgRNA target sites to chart the mutational landscape of these tumors, revealing the functional consequence of multiple variants in driving liver tumorigenesis in immunocompetent mice. AAV-mediated autochthonous CRISPR screens provide a powerful means for mapping a provisional functional cancer genome atlas of tumor suppressors in vivo.

关键词： Mapping

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Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway

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CELL REPORTS 2021年第5期34卷 108784-108784页

作者： Carrot-Zhang, Jian Yao, Xiaotong Devarakonda, Siddhartha Deshpande, Aditya Damrauer, Jeffrey S. Silva, Tiago Chedraoui Wong, Christopher K. Choi, Hyo Young Felau, Ina Robertson, A. Gordon Castro, Mauro A. A. Bao, Lisui Rheinbay, Esther Liu, Eric Minwei Trieu, Tuan Haan, David Yau, Christina Hinoue, Toshinori Liu, Yuexin Shapira, Ofer Kumar, Kiran Mungall, Karen L. Zhang, Hailei Lee, Jake June-Koo Berger, Ashton Gao, Galen F. Zhitomirsky, Binyamin Liang, Wen-Wei Zhou, Meng Moorthi, Sitapriya Berger, Alice H. Collisson, Eric A. Zody, Michael C. Ding, Li Cherniack, Andrew D. Getz, Gad Elemento, Olivier Benz, Christopher C. Stuart, Josh Zenklusen, J. C. Beroukhim, Rameen Chang, Jason C. Campbell, Joshua D. Hayes, D. Neil Yang, Lixing Laird, Peter W. Weinstein, John N. Kwiatkowski, David J. Tsao, Ming S. Travis, William D. Khurana, Ekta Berman, Benjamin P. Hoadley, Katherine A. Robine, Nicolas Meyerson, Matthew Govindan, Ramaswamy Imielinski, Marcin Dana Farber Canc Inst Boston MA 02115 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Boston MA 02115 USA Weill Cornell Med Dept Pathol & Lab Med New York NY 10065 USA New York Genome Ctr New York NY 10013 USA Triinst PhD Program Computat Biol & Med New York NY USA Washington Univ Sch Med Sect Med Oncol Div Oncol St Louis MO 63110 USA Washington Univ Siteman Canc Ctr St Louis MO 63110 USA Univ N Carolina Lineberger Comprehens Canc Ctr Dept Genet Computat Med Program Chapel Hill NC 27515 USA Cedars Sinai Med Ctr Ctr Bioinformat & Funct Genom Los Angeles CA 90048 USA Univ Calif Santa Cruz Dept Biomol Engn Santa Cruz CA 95064 USA Univ Tennessee Hlth Sci Ctr UTHSC Ctr Canc Res Knoxville TN 37996 USA NCI Bethesda MD 20892 USA BC Canc Canadas Michael Smith Genome Sci Ctr Vancouver BC Canada Univ Fed Parana Bioinformat & Syst Biol Lab Curitiba Parana Brazil Univ Chicago Ben May Dept Canc Res Chicago IL 60637 USA Massachusetts Gen Hosp Canc Ctr Boston MA 02114 USA Univ Calif San Francisco San Francisco CA 94143 USA Buck Inst Res Aging Novato CA USA Van Andel Inst Grand Rapids MI USA Univ Texas MD Anderson Canc Ctr Dept Bioinformat & Computat Biol Houston TX 77030 USA Washington Univ McDonnell Genome Inst St Louis MO USA Fred Hutchinson Canc Res Ctr 1124 Columbia St Seattle WA 98104 USA Brigham & Womens Hosp Dept Med 75 Francis St Boston MA 02115 USA Mem Sloan Kettering Canc Ctr Dept Pathol Thorac Pathol 1275 York Ave New York NY 10021 USA Boston Univ Div Computat Biomed Sch Med Boston MA USA Univ Hlth Network Princess Margaret Canc Ctr Dept Pathol Toronto ON Canada Hebrew Univ Jerusalem Inst Med Res Israel Canada Dept Dev Biol & Canc Res Jerusalem Israel Weill Cornell Med Caryl & Israel Englander Inst Precis Med & Meyer New York NY 10065 USA

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.

关键词： lung adenocarcinoma whole genome sequencing structural variation precision oncology oncogene driver TCGA noncoding genome analysis tumor suppressor

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Author Correction: Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein

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Nature communications 2024年第1期15卷 6413页

作者： Xiaobo Mao Hao Gu Donghoon Kim Yasuyoshi Kimura Ning Wang Enquan Xu Ramhari Kumbhar Xiaotian Ming Haibo Wang Chan Chen Shengnan Zhang Chunyu Jia Yuqing Liu Hetao Bian Senthilkumar S Karuppagounder Fatih Akkentli Qi Chen Longgang Jia Heehong Hwang Su Hyun Lee Xiyu Ke Michael Chang Amanda Li Jun Yang Cyrus Rastegar Manjari Sriparna Preston Ge Saurav Brahmachari Sangjune Kim Shu Zhang Yasushi Shimoda Martina Saar Haiqing Liu Sin Ho Kweon Mingyao Ying Creg J Workman Dario A A Vignali Ulrike C Muller Cong Liu Han Seok Ko Valina L Dawson Ted M Dawson Neuroregeneration and Stem Cell Programs Institute for Cell Engineering Johns Hopkins University School of Medicine Baltimore MD 21205 USA. xmao4@jhmi.edu. Department of Neurology Johns Hopkins University School of Medicine Baltimore MD 21205 USA. xmao4@jhmi.edu. Adrienne Helis Malvin Medical Research Foundation New Orleans LA 70130-2685 USA. xmao4@jhmi.edu. Neuroregeneration and Stem Cell Programs Institute for Cell Engineering Johns Hopkins University School of Medicine Baltimore MD 21205 USA. Department of Neurology Johns Hopkins University School of Medicine Baltimore MD 21205 USA. Department of Neurology Nanjing Brain Hospital Nanjing Jiangsu 210029 PR China. Medical College Yangzhou University Yangzhou Jiangsu 225001 PR China. Department of Pharmacology College of Medicine Dong-A University 32 Daesin Gongwwon-ro Seo-gu Busan 49201 Republic of Korea. Adrienne Helis Malvin Medical Research Foundation New Orleans LA 70130-2685 USA. Department of Anesthesiology West China Hospital Sichuan University. The Research Units of West China (2018RU012)-Chinese Academy of Medical Sciences West China Hospital Sichuan University Chengdu Sichuan 610041 PR China. Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences 26 Qiuyue Road Shanghai 201210 China. University of the Chinese Academy of Sciences 19 A Yuquan Road Shijingshan District Beijing 100049 China. Institute for NanoBioTechnology Johns Hopkins University Baltimore MD 21218 USA. Department of Materials Science and Engineering Whiting School of Engineering Johns Hopkins University Baltimore MD 21218 USA. Department of Brain and Cognitive Sciences Massachusetts Institute of Technology Cambridge MA 02139 USA. Picower Institute for Learning and Memory Cambridge MA 02139 USA. Harvard-MIT MD/PhD Program Harvard Medical School Boston MA 02115 USA. Department of Biological Science and Biotechnology Chungbuk Nati

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NQO1 protects obese mice through improvements in glucose and lipid metabolism

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NPJ AGING AND MECHANISMS OF DISEASE 2020年第1期6卷 13页

作者： Di Francesco, Andrea Choi, Youngshim Bernier, Michel Zhang, Yingchun Diaz-Ruiz, Alberto Aon, Miguel A. Kalafut, Krystle Ehrlich, Margaux R. Murt, Kelsey Ali, Ahmed Pearson, Kevin J. Levan, Sophie Preston, Joshua D. Martin-Montalvo, Alejandro Martindale, Jennifer L. Abdelmohsen, Kotb Michel, Cole R. Willmes, Diana M. Henke, Christine Navas, Placido Villalba, Jose Manuel Siegel, David Gorospe, Myriam Fritz, Kristofer Biswal, Shyam Ross, David de Cabo, Rafael NIA Translat Gerontol Branch Intramural Program NIH Baltimore MD 21224 USA Johns Hopkins Bloomberg Sch Publ Hlth Dept Environm Hlth Sci Baltimore MD 21205 USA Inst IMDEA Food Precis Nutr & Aging Nutr Intervent Grp Crta Canto Blanco 8 Madrid 28049 Spain Univ Kentucky Coll Med Pharmacol & Nutr Sci Lexington KY 40536 USA NIA Lab Genet & Genom Intramural Program NIH Baltimore MD 21224 USA Univ Colorado Skaggs Sch Pharm & Pharmaceut Sci Dept Pharmaceut Sci Anschutz Med Campus Aurora CO 80045 USA Tech Univ Dresden Univ Hosp Carl Gustav Carus Helmholtz German Ctr Diabet Res Munich Mol DiabetolPaul Langerhans Inst Dresden D-01307 Dresden Germany Tech Univ Dresden Fac Med D-01307 Dresden Germany Univ Pablo de Olavide CSIC JA Ctr Andaluz Biol Desarrollo Seville 41013 Spain Univ Cordoba Dept Biol Celular Fisiol & Inmunol CeiA3 Campus Excelencia Int Agroalimentario Seville Spain Calico Life Sci San Francisco CA USA Univ Maryland Sch Med Baltimore MD 21201 USA Southwest Univ Coll Pharmaceut Sci & Chinese Med Chongqing 475004 Peoples R China Harvard TH Chan Sch Publ Hlth Boston MA 02115 USA Cornell Univ Dept Food Sci Ithaca NY 14850 USA Johns Hopkins Bloomberg Sch Publ Hlth Baltimore MD 21205 USA MIT Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA Emory Univ Sch Med MD PhD Program Atlanta GA USA Univ Seville Junta de Andalucia Univ Pablo de Olavide Andalusian Ctr Mol Biol & Regenerat Med CABIMER Dept Regenerat & Cell TherapyCSIC Seville Spain

Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with and inhibition of the translational machinery in skeletal muscle of NQO1 transgenic mice. NQO1-Tg mice on high-fat diet had lower adipose tissue macrophages and enhanced expression of lipogenic enzymes coincident with reduction in circulating and hepatic lipids. Metabolomics data revealed a systemic metabolic signature of improved glucose handling, cellular redox, and NAD(+) metabolism while label-free quantitative mass spectrometry in skeletal muscle uncovered a distinct diet- and genotype-dependent acetylation pattern of SIRT3 targets across the core of intermediary metabolism. Thus, under nutritional excess, NQO1 transgenesis preserves healthful benefits.

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Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

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NATURE GENETICS 2020年第3期52卷 306-+页

作者： Rodriguez-Martin, Bernardo Alvarez, Eva G. Baez-Ortega, Adrian Zamora, Jorge Supek, Fran Demeulemeester, Jonas Santamarina, Martin Ju, Young Seok Temes, Javier Garcia-Souto, Daniel Detering, Harald Li, Yilong Rodriguez-Castro, Jorge Dueso-Barroso, Ana Bruzos, Alicia L. Dentro, Stefan C. Blanco, Miguel G. Contino, Gianmarco Ardeljan, Daniel Tojo, Marta Roberts, Nicola D. Zumalave, Sonia Edwards, Paul A. W. Weischenfeldt, Joachim Puiggros, Montserrat Chong, Zechen Chen, Ken Lee, Eunjung Alice Wala, Jeremiah A. Raine, Keiran Butler, Adam Waszak, Sebastian M. Navarro, Fabio C. P. Schumacher, Steven E. Monlong, Jean Maura, Francesco Bolli, Niccolo Bourque, Guillaume Gerstein, Mark Park, Peter J. Wedge, David C. Beroukhim, Rameen Torrents, David Korbel, Jan O. Martincorena, Inigo Fitzgerald, Rebecca C. Van Loo, Peter Kazazian, Haig H. Burns, Kathleen H. Campbell, Peter J. Tubio, Jose M. C. Akdemir, Kadir C. Boutros, Paul C. Bowtell, David D. L. Brors, Benedikt Chan, Kin Cortes-Ciriano, Isidro Dunford, Andrew J. Edwards, Paul A. Estivill, Xavier Etemadmoghadam, Dariush Feuerbach, Lars Fink, J. Lynn Frenkel-Morgenstern, Milana Garsed, Dale W. Gordenin, Dmitry A. Haan, David Haber, James E. Hess, Julian M. Hutter, Barbara Imielinski, Marcin Jones, David T. W. Kazanov, Marat D. Klimczak, Leszek J. Koh, Youngil Kumar, Kiran Lee, Jake June-Koo Lynch, Andy G. Macintyre, Geoff Markowetz, Florian Martinez-Fundichely, Alexander Meyerson, Matthew Miyano, Satoru Nakagawa, Hidewaki Ossowski, Stephan Pearson, John, V Rippe, Karsten Roberts, Steven A. Scully, Ralph Shackleton, Mark Sidiropoulos, Nikos Sieverling, Lina Stewart, Chip Villasante, Izar Waddell, Nicola Yang, Lixing Yao, Xiaotong Yoon, Sung-Soo Zhang, Cheng-Zhong Univ Santiago de Compostela Ctr Res Mol Med & Chron Dis CIMUS Genomes & Dis Santiago De Compostela Spain Univ Santiago de Compostela Dept Zool Genet & Phys Anthropol Santiago De Compostela Spain Univ Vigo Biomed Res Ctr CINBIO Vigo Spain Univ Cambridge Dept Vet Med Transmissible Canc Grp Cambridge England Barcelona Inst Sci & Technol Inst Res Biomed IRB Barcelona Genome Data Sci Barcelona Spain ICREA Barcelona Spain Francis Crick Inst London England Univ Leuven Dept Human Genet Leuven Belgium Korea Adv Inst Sci & Technol Grad Sch Med Sci & Engn Daejeon South Korea Wellcome Sanger Inst Canc Ageing & Somat Mutat Programme Cambridge England Univ Vigo Dept Biochem Genet & Immunol Vigo Spain Galicia Hlth Res Inst Vigo Spain CNS BSC Barcelona Spain Univ Vic Fac Sci & Technol Cent Univ Catalonia UVic UCC Vic Spain Wellcome Sanger Inst Expt Canc Genet Cambridge England Univ Oxford Oxford Big Data Inst Oxford England Univ Santiago de Compostela Ctr Res Mol Med & Chron Dis CIMUS DNA Repair & Genome Integr Santiago De Compostela Spain Univ Santiago de Compostela Dept Biochem & Mol Biol Santiago De Compostela Spain Univ Cambridge MRC Canc Unit Cambridge England Johns Hopkins Univ Dept Genet Med Sch Med Baltimore MD USA Univ Cambridge Dept Pathol Cambridge England Univ Cambridge Canc Res UK Cambridge Inst Cambridge England Univ Copenhagen Biotech Res & Innovat Ctr Copenhagen Denmark Rigshosp Finsen Lab Copenhagen Denmark European Mol Biol Lab Genome Biol Unit Heidelberg Germany Univ Texas MD Anderson Canc Ctr Dept Bioinformat & Computat Biol Houston TX 77030 USA Univ Alabama Birmingham Sch Med Dept Genet Birmingham AL USA Univ Alabama Birmingham Sch Med Informat Inst Birmingham AL USA Harvard Med Sch Boston Childrens Hosp Div Genet & Genom Boston MA 02115 USA Broad Inst Harvard & MIT Cambridge MA USA Dana Farber Canc Inst Dept Canc Biol Boston MA 02115 USA Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA Yale Univ Pr

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1;L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors. An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

关键词： Cancer Genomics

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Patterns of somatic structural variation in human cancer genomes

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NATURE 2020年第7793期578卷 112-+页

作者： Li, Yilong Roberts, Nicola D. Wala, Jeremiah A. Shapira, Ofer Schumacher, Steven E. Kumar, Kiran Khurana, Ekta Waszak, Sebastian Korbel, Jan O. Haber, James E. Imielinski, Marcin Weischenfeldt, Joachim Beroukhim, Rameen Campbell, Peter J. Akdemir, Kadir C. Alvarez, Eva G. Baez-Ortega, Adrian Boutros, Paul C. Bowtell, David D. L. Brors, Benedikt Burns, Kathleen H. Chan, Kin Chen, Ken Cortes-Ciriano, Isidro Dueso-Barroso, Ana Dunford, Andrew J. Edwards, Paul A. Estivill, Xavier Etemadmoghadam, Dariush Feuerbach, Lars Fink, J. Lynn Frenkel-Morgenstern, Milana Garsed, Dale W. Gerstein, Mark Gordenin, Dmitry A. Haan, David Hess, Julian M. Hutter, Barbara Jones, David T. W. Ju, Young Seok Kazanov, Marat D. Klimczak, Leszek J. Koh, Youngil Lee, Eunjung Alice Lee, Jake June-Koo Lynch, Andy G. Macintyre, Geoff Markowetz, Florian Martincorena, Inigo Martinez-Fundichely, Alexander Meyerson, Matthew Miyano, Satoru Nakagawa, Hidewaki Navarro, Fabio C. P. Ossowski, Stephan Park, Peter J. Pearson, John, V Puiggros, Montserrat Rippe, Karsten Roberts, Steven A. Rodriguez-Martin, Bernardo Scully, Ralph Shackleton, Mark Sidiropoulos, Nikos Sieverling, Lina Stewart, Chip Torrents, David Tubio, Jose M. C. Villasante, Izar Waddell, Nicola Yang, Lixing Yao, Xiaotong Yoon, Sung-Soo Zamora, Jorge Zhang, Cheng-Zhong Wellcome Trust Sanger Inst Canc Genome Project Hinxton England Totient Inc Cambridge MA USA Broad Inst Harvard & MIT Cambridge MA 02142 USA Harvard Univ Bioinformat & Integrat Genom Cambridge MA 02138 USA Dana Farber Canc Inst Dept Canc Biol Boston MA 02115 USA Weill Cornell Med Coll New York NY USA European Mol Biol Lab Genome Biol Unit Heidelberg Germany Brandeis Univ Rosenstiel Basic Med Sci Res Ctr Dept Mol Biol Waltham MA 02254 USA New York Genome Ctr New York NY USA Univ Copenhagen Rigshosp Biotech Res & Innovat Ctr BRIC Finsen Lab Copenhagen Denmark Univ Cambridge Dept Haematol Cambridge England Univ Texas MD Anderson Canc Ctr Houston TX 77030 USA Univ Santiago de Compostela Dept Zool Genet & Phys Anthropol Santiago De Compostela Spain Univ Santiago de Compostela Ctr Res Mol Med & Chron Dis CIMUS Santiago De Compostela Spain Univ Vigo Biomed Res Ctr CINBIO Vigo Spain Univ Cambridge Dept Vet Med Transmissible Canc Grp Cambridge England Ontario Inst Canc Res Computat Biol Program Toronto ON Canada Univ Toronto Dept Med Biophys Toronto ON Canada Univ Toronto Dept Pharmacol Toronto ON Canada Univ Calif Los Angeles Los Angeles CA USA Peter MacCallum Canc Ctr Melbourne Vic Australia Univ Melbourne Sir Peter MacCallum Dept Oncol Melbourne Vic Australia Natl Ctr Tumor Dis NCT Heidelberg Heidelberg Germany German Canc Res Ctr Div Appl Bioinformat Heidelberg Germany German Canc Res Ctr German Canc Consortium DKTK Heidelberg Germany Johns Hopkins Sch Med Baltimore MD USA Univ Ottawa Fac Med Dept Biochem Microbiol & Immunol Ottawa ON Canada Univ Cambridge Ctr Mol Sci Informat Dept Chem Cambridge England Harvard Med Sch Dept Biomed Informat Boston MA 02115 USA Harvard Med Sch Ludwig Ctr Boston MA 02115 USA Barcelona Supercomp Ctr BSC Barcelona Spain Univ Cambridge Canc Res UK Cambridge Inst Cambridge England Univ Cambridge Cambridge England Sidra Med Doha Qatar Univ Queensland Queensland Ctr Med Genom Inst Mol Biosci

A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes(1-7). Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types(8). Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions-as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2-7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and-in liver cancerfrequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

关键词： Cancer genomics Genomic instability

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