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Interferon-ε loss is elusive 9p21 link to immune-cold tumors, resistant to immune-checkpoint therapy and endogenous CXCL9/10 induction

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Journal of thoracic oncology : official publication of the International Association for the Study of Lung cancer 2024年

作者： Xin Zhao Bin Liu William N William Kaloyan M Tsanov Yu-Jui Ho Francisco M Barriga Raymond J Lim Maria Trifas Yushen Du Scott W Lowe Steven M Dubinett Teresa Davoli Scott M Lippman Department of Biochemistry and Molecular Pharmacology Institute for Systems Genetics New York University Langone Health New York NY 10016 USA. Division of Pulmonary and Critical Care Department of Medicine David Geffen School of Medicine at UCLA Los Angeles California USA. Grupo Oncoclínicas São Paulo Brazil Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 Moores Cancer Center University of California San Diego La Jolla CA 92037 Department of Medicine University of California San Diego La Jolla CA 92037 USA. Cancer Biology & Genetics Program Memorial Sloan Kettering Cancer Center New York NY USA. Cancer Institute The Second Affiliated Hospital Zhejiang University School of Medicine 866 Yuhangtang Rd Hangzhou Zhejiang 310058 China. Cancer Biology & Genetics Program Memorial Sloan Kettering Cancer Center New York NY USA Howard Hughes Medical Institute Chevy Chase MD USA. Department of Medicine Department of Pathology and Laboratory Medicine Department of and Molecular and Medical Pharmacology David Geffen School of Medicine at UCLA Los Angeles California UCLA Jonsson Comprehensive Cancer Center USA. Moores Cancer Center University of California San Diego La Jolla CA 92037 USA Department of Medicine University of California San Diego La Jolla CA 92037 USA Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA.

INTRODUCTION:Copy-number (CN) loss of chromosome 9p, or parts thereof, impair immune response and confer ICT resistance by direct elimination of immune-regulatory genes on this arm, notably IFNγ genes at 9p24.1, and type-I interferon (IFN-I) genes at 9p21.3. We recently found that the primary 9p-loss human-tumor immune readout, however, is indirect (CXCL9/10 depletion at 4q21.1), and in mice, uncovered little-studied IFN-I interferon-ε (IFNϵ) deletion as the pivotal 9p21.3 link to TME immune-cell suppression. The central role of CXCL9 and/or CXCL10 in TME, has generated intense interest in cellular sources and regulation of these chemokines. We developed a focal gene-deletion strategy, termed MACHETE, to study the contribution of individual IFN-I genes to TME immune-cell populations in murine models. In this report, MACHETE-engineered deletions of Cdkn2a/b alone, MTAP vs Cdkn2a/b with progressively increasing numbers of IFN-I genes, ΔS and ΔL, at mouse chr4C4 syntenic to human chr9p21.3, were used to assess IFN-I contribution of to cxcl9 and cxcl10 expression levels. METHODS:This research perspective updates and explicates the rapidly emerging body of clinical 9p CN alteration (CNA)/ICT data (13 reports, 36 cohorts, 3.5 years), and executes clinical and experimental 9p, IFNϵ and CXCL9/10 studies of this novel genomic ICT-resistance mechanism. We analyzed 9p, 9p21.3 and 9p24.1 influence on IFN-I gene-expression and using CIBERSORT, Kassandra, MCPcounter, xCell immune-cell deconvolution probed CD8 T-cells, dendritic cells (DCs), macrophages, neutrophils; subtypes, molecules, and sub-cluster mechanisms in HPV HNSC (TCGA, n=343; CPTAC (n=105) and 32 cell lines, and pancreatic ductal adenocarcinoma (PDAC) (177 TCGA, 44 lines). We also include pan (34)-tumor analysis, focused on 4 highly aneuploid tumors-HPV HNSC, NSCLC (non-squamous [NS) and squamous [LUSC]), and PDAC-and mouse-model PDAC and NS NSCLC studies. To identify CXCL9/10-CXCR3 axis sources and regulation, we an

关键词： chemokines chromosome 9p genomic copy number alterations immunotherapy interferons

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Author Correction: Compilation of longitudinal microbiota data and hospitalome from hematopoietic cell transplantation patients

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Scientific data 2021年第1期8卷 119页

作者： Chen Liao Bradford P Taylor Camilla Ceccarani Emily Fontana Luigi A Amoretti Roberta J Wright Antonio L C Gomes Jonathan U Peled Ying Taur Miguel-Angel Perales Marcel R M van den Brink Eric Littmann Eric G Pamer Jonas Schluter Joao B Xavier Program for Computational and Systems Biology Memorial Sloan-Kettering Cancer Center New York NY USA. Department of Health Sciences Università degli Studi di Milano Milan Italy. Infectious Disease Service Department of Medicine and Immunology Program Sloan Kettering Institute New York NY USA. Department of Immunology Memorial Sloan-Kettering Cancer Center New York NY USA. Adult Bone Marrow Transplantation Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA. Weill Cornell Medical College New York NY USA. Duchossois Family Institute University of Chicago Chicago IL USA. Program for Computational and Systems Biology Memorial Sloan-Kettering Cancer Center New York NY USA. jonas.schluter@***. Program for Computational and Systems Biology Memorial Sloan-Kettering Cancer Center New York NY USA. xavierj@***.

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LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition

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细胞研究（英文版） 2019年第4期29卷 286-304页

作者： Qingsong Hu Chunlai Li Shouyu Wang Yajuan Li Bo Wen Yanyan Zhang Ke Liang Jun Yao Youqiong Ye Heidi Hsiao Tina K.Nguyen Peter K.Park Sergey D.Egranov David H.Hawke Jeffrey R.Marks Leng Han Mien-Chie Hung Bing Zhang Chunru Lin Liuqing Yang Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of hepatobiliary Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing Jiangsu Province China Department of Molecular and Human Genetics Baylor College of Medicine Houston TX 77030 USA Lester and Sue Smith Breast Center Baylor College of Medicine Houston TX 77030 USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Institute of Immunology Third Military Medical University 400038 Chongqing China Department of Biochemistry and Molecular Biology The University of Texas Health Science Center at Houston McGroven Medical School Houston TX 77030 USA Department of Systems Biology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Surgery Duke University School of Medicine Durham NC 27710 USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA program in Cancer Biology Graduate School of Biomedical Sciences The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA program in Cancer Biology Graduate School of Biomedical Sciences The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Center for RNA Interference and Non-Coding RNAs The University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Despite the structural consenvation of PTEN with dual-specificity phosphatases,there have been no reports regarding the regulatory mechanisms that underlie this potential dual-phosphatase ***,we report that K27-linked polyubiquitination of PTEN at lysines 66 and 80 switches its phosphoinositide/protein tyrosine phosphatase activity to protein serine/threonine phosphatase ***,high glucose,TGF-β,CTGF,SHH,and IL-6 induce the expression of a long non-coding RNA,GAEA (Glucose Aroused for EMT Activation),which associates with an RNA-binding E3 ligase,MEX3C,and enhances its enzymatic activity,leading to the K27-linked polyubiquitination of *** MEX3C-catalyzed PTENK27-polyUb activates its protein serine/threonine phosphatase activity and inhibits its phosphatidylinositol/protein tyrosine phosphatase *** this altered enzymatic activity,PTENK27-polyub dephosphorylates the phosphoserine/threonine residues of TWlST1,SNAI1,and YAP1,leading to accumulation of these master regulators of *** with genetic inhibition of PTENK27polyUb,by a single nucieotide mutation generated using CRISPR/Cas9 (PtenK80R/K80R),exhibit inhibition of EMT markers during mammary gland morphogenesis in pregnancy/lactation and during cutaneous wound healing *** findings illustrate an unexpected paradigm in which the IncRNA-dependent switch in PTEN protein serine/threonine phosphatase activity is important for physiological homeostasis and disease development.

关键词： Epithelial-mesenchymal transition Long non-coding RNAs Ubiquitylation

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Publisher Correction: Predicting functional consequences of mutations using molecular interaction network features

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Human genetics 2022年第10期141卷 1593页

作者： Kivilcim Ozturk Hannah Carter Division of Medical Genetics Department of Medicine University of California San Diego La Jolla CA USA. Bioinformatics and Systems Biology Program University of California San Diego La Jolla CA USA. Division of Medical Genetics Department of Medicine University of California San Diego La Jolla CA USA. hkcarter@health.ucsd.edu. Bioinformatics and Systems Biology Program University of California San Diego La Jolla CA USA. hkcarter@health.ucsd.edu. Moores Cancer Center University of California San Diego La Jolla CA USA. hkcarter@health.ucsd.edu.

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Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

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Nature genetics 2023年第3期55卷 519-520页

作者： Ceres Fernandez-Rozadilla Maria Timofeeva Zhishan Chen Philip Law Minta Thomas Stephanie Schmit Virginia Díez-Obrero Li Hsu Juan Fernandez-Tajes Claire Palles Kitty Sherwood Sarah Briggs Victoria Svinti Kevin Donnelly Susan Farrington James Blackmur Peter Vaughan-Shaw Xiao-Ou Shu Jirong Long Qiuyin Cai Xingyi Guo Yingchang Lu Peter Broderick James Studd Jeroen Huyghe Tabitha Harrison David Conti Christopher Dampier Mathew Devall Fredrick Schumacher Marilena Melas Gad Rennert Mireia Obón-Santacana Vicente Martín-Sánchez Ferran Moratalla-Navarro Jae Hwan Oh Jeongseon Kim Sun Ha Jee Keum Ji Jung Sun-Seog Kweon Min-Ho Shin Aesun Shin Yoon-Ok Ahn Dong-Hyun Kim Isao Oze Wanqing Wen Keitaro Matsuo Koichi Matsuda Chizu Tanikawa Zefang Ren Yu-Tang Gao Wei-Hua Jia John Hopper Mark Jenkins Aung Ko Win Rish Pai Jane Figueiredo Robert Haile Steven Gallinger Michael Woods Polly Newcomb David Duggan Jeremy Cheadle Richard Kaplan Timothy Maughan Rachel Kerr David Kerr Iva Kirac Jan Böhm Lukka-Pekka Mecklin Pekka Jousilahti Paul Knekt Lauri Aaltonen Harri Rissanen Eero Pukkala Johan Eriksson Tatiana Cajuso Ulrika Hänninen Johanna Kondelin Kimmo Palin Tomas Tanskanen Laura Renkonen-Sinisalo Brent Zanke Satu Männistö Demetrius Albanes Stephanie Weinstein Edward Ruiz-Narvaez Julie Palmer Daniel Buchanan Elizabeth Platz Kala Visvanathan Cornelia Ulrich Erin Siegel Stefanie Brezina Andrea Gsur Peter Campbell Jenny Chang-Claude Michael Hoffmeister Hermann Brenner Martha Slattery John Potter Konstantinos Tsilidis Matthias Schulze Marc Gunter Neil Murphy Antoni Castells Sergi Castellví-Bel Leticia Moreira Volker Arndt Anna Shcherbina Mariana Stern Bens Pardamean Timothy Bishop Graham Giles Melissa Southey Gregory Idos Kevin McDonnell Zomoroda Abu-Ful Joel Greenson Katerina Shulman Flavio Lejbkowicz Kenneth Offit Yu-Ru Su Robert Steinfelder Temitope Keku Bethany van Guelpen Thomas Hudson Heather Hampel Rachel Pearlman Sonja Berndt Richard Hayes Marie Elena Martinez Sushma Thomas Douglas Corley Paul Pharoah Susanna Larsson Yun Yen Heinz-Jo Edinburgh Cancer Research Centre Institute of Genomics and Cancer University of Edinburgh Edinburgh UK. Genomic Medicine Group Instituto de Investigacion Sanitaria de Santiago Santiago de Compostela Spain. Colon Cancer Genetics Group Medical Research Council Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh UK. Danish Institute for Advanced Study Department of Public Health University of Southern Denmark Odense Denmark. Division of Epidemiology Department of Medicine Vanderbilt-Ingram Cancer Center Vanderbilt Epidemiology Center Vanderbilt University Medical Center Nashville TN USA. Division of Genetics and Epidemiology Institute of Cancer Research London UK. Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA. Genomic Medicine Institute Cleveland Clinic Cleveland OH USA. Population and Cancer Prevention Program Case Comprehensive Cancer Center Cleveland OH USA. Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute Barcelona Spain. Oncology Data Analytics Program Catalan Institute of Oncology Barcelona Spain. Consortium for Biomedical Research in Epidemiology and Public Health Madrid Madrid Spain. Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain. Department of Biostatistics School of Public Health University of Washington Seattle WA USA. Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham UK. Department of Public Health Richard Doll Building University of Oxford Oxford UK. Department of Biomedical Informatics Vanderbilt University School of Medicine Nashville TN USA. Department of Preventive Medicine USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles CA USA. Center for Public Health Genomics Department of Public Health Sciences University of Virginia Charlottesville VA USA. De

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Correction to: CpG‑creating mutations are costly in many human viruses

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Evolutionary Ecology 2020年第3期34卷 361-362页

作者： Caudill, Victoria R. Qin, Sarina Winstead, Ryan Kaur, Jasmeen Tisthammer, Kaho Pineda, E. Geo Solis, Caroline Cobey, Sarah Bedford, Trevor Carja, Oana Eggo, Rosalind M. Koelle, Katia Lythgoe, Katrina Regoes, Roland Roy, Scott Allen, Nicole Aviles, Milo Baker, Brittany A. Bauer, William Bermudez, Shannel Carlson, Corey Castellanos, Edgar Catalan, Francisca L. Chemel, Angeline Katia Elliot, Jacob Evans, Dwayne Fiutek, Natalie Fryer, Emily Goodfellow, Samuel Melvin Hecht, Mordecai Hopp, Kellen Hopson, E. Deshawn Jaberi, Amirhossein Kim, Jennifer Kinney, Christen Lao, Derek Le, Adrienne Lo, Jacky Lopez, Alejandro G. López, Andrea Lorenzo, Fernando G. Luu, Gordon T. Mahoney, Andrew R. Melton, Rebecca L. Nascimento, Gabriela Do Pradhananga, Anjani Rodrigues, Nicole S. Shieh, Annie Sims, Jasmine Singh, Rima Sulaeman, Hasan Thu, Ricky Tran, Krystal Tran, Livia Winters, Elizabeth J. Wong, Albert Pennings, Pleuni S. Department of Biology San Francisco State University San Francisco USA Department of Biology University of Oregon Eugene USA Quantitative Systems Biology Univeristy of California Merced USA Department of Ecology and Evolution University of Chicago Chicago USA Vaccine and Infectious Disease Division Fred Hutchinson Cancer Research Center Seattle USA Department of Computational Biology School of Computer Science Carnegie Mellon University Pittsburgh USA Department of Infectious Disease Epidemiology London School of Hygiene & Tropical Medicine London UK Department of Biology Emory University Atlanta USA Big Data Institute University of Oxford Oxford UK Department of Environmental Systems Science ETH Zurich Zurich Switzerland Department of Neurological Surgery University of California San Francisco USA Department of Organismic and Evolutionary Biology Harvard University Cambridge USA Department of Plant Biology Carnegie Institution for Science Stanford USA Health Sciences Center University of New Mexico Albuquerque USA UCSD Biomed Sciences PhD Program University of California San Diego USA Biochemistry Molecular Cellular and Developmental Biology Graduate Group University of California Davis USA UCSF Tetrad Graduate Program University of California San Francisco USA

In the original article, the co-author name "Jennifer Kim" has been inadvertently missed during the publication process. The complete author group is given in this correction.

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Publisher Correction: Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors

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Nature genetics 2023年第1期55卷 166页

作者： Huipeng Li Elise T Courtois Debarka Sengupta Yuliana Tan Kok Hao Chen Jolene Jie Lin Goh Say Li Kong Clarinda Chua Lim Kiat Hon Wah Siew Tan Mark Wong Paul Jongjoon Choi Lawrence J K Wee Axel M Hillmer Iain Beehuat Tan Paul Robson Shyam Prabhakar Computational and Systems Biology Genome Institute of Singapore Singapore Singapore. Developmental Cellomics Laboratory Genome Institute of Singapore Singapore Singapore. Department of Computer Science and Engineering and Center for Computational Biology Indraprastha Institute of Information Technology Delhi India. Synthetic Biology Genome Institute of Singapore Singapore Singapore. Cancer Therapeutics and Stratified Oncology Genome Institute of Singapore Singapore Singapore. Department of Medical Oncology National Cancer Centre Singapore Singapore Singapore. Department of Pathology Singapore General Hospital Singapore Singapore. Department of Colorectal Surgery Singapore General Hospital Singapore Singapore. Data Analytics Department Institute for Infocomm Research Singapore Singapore. Cancer Therapeutics and Stratified Oncology Genome Institute of Singapore Singapore Singapore. iain.tan.b.h@singhealth.com.sg. Department of Medical Oncology National Cancer Centre Singapore Singapore Singapore. iain.tan.b.h@singhealth.com.sg. Program in Cancer and Stem Cell Biology Duke-NUS Medical School Singapore Singapore. iain.tan.b.h@singhealth.com.sg. Developmental Cellomics Laboratory Genome Institute of Singapore Singapore Singapore. paul.robson@***. The Jackson Laboratory for Genomic Medicine Farmington Connecticut USA. paul.robson@***. Department of Genetics and Genome Sciences Institute for Systems Genomics University of Connecticut Farmington Connecticut USA. paul.robson@***. Department of Biological Sciences National University of Singapore Singapore Singapore. paul.robson@***. Computational and Systems Biology Genome Institute of Singapore Singapore Singapore. prabhakars@gis.a-star.edu.sg.

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Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk

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European journal of human genetics : EJHG 2022年第5期30卷 630-631页

作者： Eileen O Dareng Jonathan P Tyrer Daniel R Barnes Michelle R Jones Xin Yang Katja K H Aben Muriel A Adank Simona Agata Irene L Andrulis Hoda Anton-Culver Natalia N Antonenkova Gerasimos Aravantinos Banu K Arun Annelie Augustinsson Judith Balmaña Elisa V Bandera Rosa B Barkardottir Daniel Barrowdale Matthias W Beckmann Alicia Beeghly-Fadiel Javier Benitez Marina Bermisheva Marcus Q Bernardini Line Bjorge Amanda Black Natalia V Bogdanova Bernardo Bonanni Ake Borg James D Brenton Agnieszka Budzilowska Ralf Butzow Saundra S Buys Hui Cai Maria A Caligo Ian Campbell Rikki Cannioto Hayley Cassingham Jenny Chang-Claude Stephen J Chanock Kexin Chen Yoke-Eng Chiew Wendy K Chung Kathleen B M Claes Sarah Colonna Linda S Cook Fergus J Couch Mary B Daly Fanny Dao Eleanor Davies Miguel de la Hoya Robin de Putter Joe Dennis Allison DePersia Peter Devilee Orland Diez Yuan Chun Ding Jennifer A Doherty Susan M Domchek Thilo Dörk Andreas du Bois Matthias Dürst Diana M Eccles Heather A Eliassen Christoph Engel Gareth D Evans Peter A Fasching James M Flanagan Renée T Fortner Eva Machackova Eitan Friedman Patricia A Ganz Judy Garber Francesca Gensini Graham G Giles Gord Glendon Andrew K Godwin Marc T Goodman Mark H Greene Jacek Gronwald Eric Hahnen Christopher A Haiman Niclas Håkansson Ute Hamann Thomas V O Hansen Holly R Harris Mikael Hartman Florian Heitz Michelle A T Hildebrandt Estrid Høgdall Claus K Høgdall John L Hopper Ruea-Yea Huang Chad Huff Peter J Hulick David G Huntsman Evgeny N Imyanitov Claudine Isaacs Anna Jakubowska Paul A James Ramunas Janavicius Allan Jensen Oskar Th Johannsson Esther M John Michael E Jones Daehee Kang Beth Y Karlan Anthony Karnezis Linda E Kelemen Elza Khusnutdinova Lambertus A Kiemeney Byoung-Gie Kim Susanne K Kjaer Ian Komenaka Jolanta Kupryjanczyk Allison W Kurian Ava Kwong Diether Lambrechts Melissa C Larson Conxi Lazaro Nhu D Le Goska Leslie Jenny Lester Fabienne Lesueur Douglas A Levine Lian Li Jingmei Li Jennifer T Loud Karen H Lu Jan Lubiński Phuong L Mai Siranoush Manoukian Jeffrey R Marks Ra University of Cambridge Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care Cambridge UK. University of Cambridge Centre for Cancer Genetic Epidemiology Department of Oncology Cambridge UK. Center for Bioinformatics and Functional Genomics Cedars-Sinai Medical Center Los Angeles CA USA. Radboud University Medical Center Radboud Institute for Health Sciences Nijmegen The Netherlands. Netherlands Comprehensive Cancer Organisation Utrecht The Netherlands. The Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital Family Cancer Clinic Amsterdam The Netherlands. Veneto Institute of Oncology IOV-IRCCS Immunology and Molecular Oncology Unit Padua Italy. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital Fred A. Litwin Center for Cancer Genetics Toronto ON Canada. University of Toronto Department of Molecular Genetics Toronto ON Canada. University of California Irvine Department of Epidemiology Genetic Epidemiology Research Institute Irvine CA USA. N.N. Alexandrov Research Institute of Oncology and Medical Radiology Minsk Belarus. 'Agii Anargiri' Cancer Hospital Athens Greece. University of Texas MD Anderson Cancer Center Department of Breast Medical Oncology Houston TX USA. Lund University Department of Cancer Epidemiology Clinical Sciences Lund Sweden. Vall d'Hebron Institute of Oncology Hereditary cancer Genetics Group Barcelona Spain. University Hospital of Vall d'Hebron Department of Medical Oncology Barcelona Spain. Rutgers Cancer Institute of New Jersey Cancer Prevention and Control Program New Brunswick NJ USA. Landspitali University Hospital Department of Pathology Reykjavik Iceland. University of Iceland BMC (Biomedical Centre) Faculty of Medicine Reykjavik Iceland. University Hospital Erlangen Friedrich-Alexander-University Erlangen-Nuremberg Department of Gynecology and Obstetrics Comprehensive Cancer Center ER-EMN Erlangen Germany. Vanderbilt University School of Medicine Division of Epide

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Perspective on recent developments and challenges in regulatory and systems genomics

arXiv

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arXiv 2024年

作者： Zeiltinger, Julia Roy, Sushmita Ay, Ferhat Mathelier, Anthony Medina-Rivera, Alejandra Mahony, Shaun Sinha, Saurabh Ernst, Jason Stowers Institute for Medical Research Kansas CityMO64112 United States Department of Pathology & Laboratory Medicine The University of Kansas Medical Center Kansas CityKS66160 United States Department of Biostatistics and Medical Informatics University of Wisconsin-Madison Madison53715 United States Wisconsin Institute for Discovery University of Wisconsin-Madison Madison53715 United States Centers for Autoimmunity Inflammation and Cancer Immunotherapy La Jolla Institute for Immunology La Jolla CA United States Bioinformatics and Systems Biology Program University of California La Jolla San DiegoCA United States Department of Pediatrics University of California La Jolla San DiegoCA United States Nordic EMBL Partnership University of Oslo Oslo0318 Norway Department of Medical Genetics Institute of Clinical Medicine University of Oslo Oslo University Hospital Oslo Norway Department of Pharmacy University of Oslo Oslo Norway Laboratorio Internacional de Investigación sobre el Genoma Humano Universidad Nacional Autónoma de México Campus Juriquilla Blvd. Juriquilla 3001 Santiago de Querétaro76230 Mexico Center for Eukaryotic Gene Regulation Department of Biochemistry and Molecular Biology The Pennsylvania State University University ParkPA16802 United States Walter H. Coulter Department of Biomedical Engineering Georgia Institute of Technology AtlantaGA United States H. Milton Stewart School of Industrial and Systems Engineering Georgia Institute of Technology AtlantaGA United States Department of Biological Chemistry University of California Los Angeles Los AngelesCA90095 United States Computer Science Department University of California Los Angeles Los AngelesCA90095 United States Department of Computational Medicine University of California Los Angeles Los AngelesCA90095 United States Eli and Edythe Broad Center of Regenerative Medicine Stem Cell Research University of California Los Angeles Los AngelesCA90095 United States

Predicting how genetic variation affects phenotypic outcomes at the organismal, cellular, and molecular levels requires deciphering the cis-regulatory code, the sequence rules by which non-coding regions regulate genes. In this perspective, we discuss recent computational progress and challenges towards solving this fundamental problem. We describe how cis-regulatory elements are mapped and how their sequence rules can be learned and interpreted with sequence-to-function neural networks, with the goal of identifying genetic variants in human disease. We also discuss how studies of the 3D chromatin organization could help identifying long-range regulatory effects and how current methods for mapping gene regulatory networks could better describe biological processes. We point out current gaps in knowledge along with technical limitations and benchmarking challenges of computational methods. Finally, we discuss newly emerging technologies, such as spatial transcriptomics, and outline strategies for creating a more general model of the cis-regulatory code that is more broadly applicable across cell types and individuals. © 2024, CC BY-NC-SA.

关键词： Molecular docking

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Development of diagnostic and prognostic molecular biomarkers in hepatocellular carcinoma using machine learning: A systematic review

Liver Cancer International

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Liver cancer International 2023年第4期3卷

作者： Amanpreet Brar Alice Zhu Cristina Baciu Divya Sharma Wei Xu Ani Orchanian-Cheff Bo Wang Jüri Reimand Robert Grant Mamatha Bhat Department of Surgery University of Toronto Toronto Canada Ajmera Transplant Program University Health Network Toronto General Hospital Toronto Canada Department of Biostatistics Dalla Lana School of Public Health Princess Margaret Cancer Centre University Health Network Toronto Ontario Canada Library and Information Services University Health Network Toronto Ontario Canada Vector Institute for Artificial Intelligence University of Toronto Toronto Canada Computational Biology Program Ontario Institute for Cancer Research Toronto Canada Department of Medical Biophysics University of Toronto Toronto Canada Department of Molecular Genetics University of Toronto Toronto Canada Department of Medical Oncology Princess Margaret Cancer Centre University Health Network Toronto Ontario Canada Division of Gastroenterology & Hepatology Department of Medicine Temerty Faculty of Medicine University of Toronto Toronto Canada

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality and morbidity worldwide. Machine learning (ML) tools have been developed in recent years to generate diagnostic and prognostic molecular biomarkers for this high-fatality cancer. To delineate the landscape of ML in HCC, we performed a systematic search of Ovid Medline, Ovid Embase, Cochrane Database of Systematic Reviews (Ovid) and Cochrane CENTRAL (Ovid) to identify studies of HCC molecular biomarkers using ML strategies. In total, 75 studies met our inclusion criteria, 53 of which were pertinent to diagnosis of HCC and 22 of which were pertinent to prognostication of HCC. Genomic, transcriptomic, epigenomic, proteomic and metabolomic signatures were derived using various ML techniques (supervised, unsupervised and deep learning approaches) using serum, urine and tissue samples of HCC. The ML algorithms achieved a sensitivity of up to 95% for the diagnosis of HCC. Through pathway analysis of the signatures derived by ML tools, we identified regulators of epithelial-mesenchymal transition and the cancer pathway Ras/Raf/MAPK as being particularly prognostic of HCC outcome. The application of ML to molecular data in HCC has thus far resulted in the generation of highly sensitive diagnostic and prognostic signatures. In future, development of ML algorithms that incorporate clinical, laboratory, alongside molecular features will be needed to fulfil the promise of personalized HCC diagnosis and treatment.

关键词： diagnostic marker hepatocellular carcinoma machine learning molecular markers prognostic marker

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