检索结果-内蒙古大学图书馆

Custom CRISPR-Cas9 PAM variants via scalable engineering and machine learning

Nature 2025年 2025 Apr 22页

作者： Rachel A Silverstein Nahye Kim Ann-Sophie Kroell Russell T Walton Justin Delano Rossano M Butcher Martin Pacesa Blaire K Smith Kathleen A Christie Leillani L Ha Ronald J Meis Aaron B Clark Aviv D Spinner Cicera R Lazzarotto Yichao Li Azusa Matsubara Elizabeth O Urbina Gary A Dahl Bruno E Correia Debora S Marks Shengdar Q Tsai Luca Pinello Suk See De Ravin Qin Liu Benjamin P Kleinstiver PhD Program in Biological and Biomedical Sciences Harvard Medical School Boston MA USA. Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. Department of Pathology Massachusetts General Hospital Boston MA USA. Department of Pathology Harvard Medical School Boston MA USA. Institute of Pharmacy and Molecular Biotechnology (IPMB) Faculty of Engineering Sciences Heidelberg University Heidelberg Germany. Department of Biomedical Informatics Harvard Medical School Boston MA USA. Molecular Pathology Unit Massachusetts General Hospital Charlestown MA USA. Krantz Family Center for Cancer Research Massachusetts General Hospital Charlestown Charlestown MA USA. Broad Institute of Harvard and MIT Cambridge MA USA. Ocular Genomics Institute Massachusetts Eye and Ear Boston MA USA. Department of Ophthalmology Harvard Medical School Boston MA USA. Laboratory of Protein Design and Immunoengineering École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics Lausanne Switzerland. CELLSCRIPTTM Madison WI USA. Department of Systems Biology Harvard Medical School Boston MA USA. Department of Hematology St. Jude Children's Research Hospital Memphis TN USA. Laboratory of Clinical Immunology and Microbiology National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA. Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. bkleinstiver@mgh.harvard.edu. Department of Pathology Massachusetts General Hospital Boston MA USA. bkleinstiver@mgh.harvard.edu. Department of Pathology Harvard Medical School Boston MA USA. bkleinstiver@mgh.harvard.edu.

Engineering and characterizing proteins can be time-consuming and cumbersome, motivating the development of generalist CRISPR-Cas enzymes to enable diverse genome editing applications. However, such enzymes have caveats such as an increased risk of off-target editing. To enable scalable reprogramming of Cas9 enzymes, here we combined high-throughput protein engineering with machine learning (ML) to derive bespoke editors more uniquely suited to specific targets. Via structure/function-informed saturation mutagenesis and bacterial selections, we obtained nearly 1,000 engineered SpCas9 enzymes and characterized their protospacer-adjacent motif (PAM) requirements to train a neural network that relates amino acid sequence to PAM specificity. By utilizing the resulting PAM ML algorithm (PAMmla) to predict the PAMs of 64 million SpCas9 enzymes, we identified efficacious and specific enzymes that outperform evolution-based and engineered SpCas9 enzymes as nucleases and base editors in human cells while reducing off-targets. An in silico directed evolution method enables user-directed Cas9 enzyme design, including for allele-selective targeting of the RHO P23H allele in human cells and mice. Together, PAMmla integrates ML and protein engineering to curate a catalog of SpCas9 enzymes with distinct PAM requirements, and motivates the use of efficient and safe bespoke Cas9 enzymes instead of generalist enzymes for various applications.

关键词：

来源：评论

学校读者我要写书评

暂无评论

Author Correction: CRISPRi enables isoform-specific loss-of-function screens and identification of gastric cancer-specific isoform dependencies

引用

Genome biology 2021年第1期22卷 88页

作者： Rebecca Davies Ling Liu Sheng Taotao Natasha Tuano Richa Chaturvedi Kie Kyon Huang Catherine Itman Amit Mandoli Aditi Qamra Changyuan Hu David Powell Roger J Daly Patrick Tan Joseph Rosenbluh Cancer Research Program and Department of Biochemistry and Molecular Biology Biomedicine Discovery Institute Monash University Clayton VIC 3800 Australia. Program in Cancer and Stem Cell Biology Duke-NUS Medical School Singapore 169857 Singapore. Cancer Science Institute of Singapore National University of Singapore Singapore 117599 Singapore. Cancer Therapeutics and Stratified Oncology Genome Institute of Singapore Singapore 138672 Singapore. SingHealth/Duke-NUS Institute of Precision Medicine National Heart Centre Singapore Singapore 169856 Singapore. Cellular and Molecular Research National Cancer Centre Singapore 169610 Singapore. Singapore Gastric Cancer Consortium Singapore 119074 Singapore. Functional Genomics Platform Monash University Clayton VIC 3800 Australia. Monash Bioinformatics Platform Monash University Clayton VIC 3800 Australia. Program in Cancer and Stem Cell Biology Duke-NUS Medical School Singapore 169857 Singapore. gmstanp@dukenus.edu.sg. Cancer Science Institute of Singapore National University of Singapore Singapore 117599 Singapore. gmstanp@dukenus.edu.sg. Cancer Therapeutics and Stratified Oncology Genome Institute of Singapore Singapore 138672 Singapore. gmstanp@dukenus.edu.sg. SingHealth/Duke-NUS Institute of Precision Medicine National Heart Centre Singapore Singapore 169856 Singapore. gmstanp@dukenus.edu.sg. Cellular and Molecular Research National Cancer Centre Singapore 169610 Singapore. gmstanp@dukenus.edu.sg. Singapore Gastric Cancer Consortium Singapore 119074 Singapore. gmstanp@dukenus.edu.sg. Cancer Research Program and Department of Biochemistry and Molecular Biology Biomedicine Discovery Institute Monash University Clayton VIC 3800 Australia. sefi.rosenbluh@monash.edu. Functional Genomics Platform Monash University Clayton VIC 3800 Australia. sefi.rosenbluh@monash.edu.

An amendment to this paper has been published and can be accessed via the original article.

关键词：

来源：评论

学校读者我要写书评

暂无评论

Resurgence of Syphilis in the United States: An Assessment of Contributing Factors

引用

Infectious diseases 2019年 12卷 1178633719883282页

作者： Rebecca Schmidt Paul James Carson Rick J Jansen Department of Public Health North Dakota State University Fargo ND USA. Center for Immunization Research and Education North Dakota State University Fargo ND USA. Biostatistics Core Facility North Dakota State University Fargo ND USA. Genomics and Bioinformatics Program North Dakota State University Fargo ND USA.

In the last decade, there has been a marked resurgence of syphilis in the United States despite the availability of effective treatments and previously reliable prevention strategies. The majority of cases are among the population of men who have sex with men (MSM); however, there has also been a recent increase among premenopausal women, coinciding with a concerning rise of congenital cases. The resurgence of syphilis can be largely attributed to changing social and behavioral factors, especially among young MSM. The biological association of syphilis with human immunodeficiency virus (HIV) transmission and acquisition is particularly alarming because of the increased individual and healthcare burden. In addition, some individual actions and public health efforts that are meant to reduce the risk of acquiring HIV may actually lead to risk compensation that facilitates the transmission of syphilis. Untreated syphilis is associated with detrimental health outcomes; therefore, both effective prevention strategies and treatment of this systemic disease have important short-term and long-term public health implications. This article offers a review of social and behavioral factors contributing to the current resurgence and recommendations for reducing syphilis incidence through medical and public health prevention strategies.

关键词： HIV coinfection HIV risk compensation Illicit drug abuse men who have sex with men sexual behavior sexually transmitted infection syphilis incidence

来源：评论

学校读者我要写书评

暂无评论

Author Correction: Whole genome sequencing reveals the impact of recent artificial selection on red sea bream reared in fish farms

引用

Scientific reports 2020年第1期10卷 1625页

作者： Bo-Hye Nam DongAhn Yoo Young-Ok Kim Jung Youn Park Younhee Shin Ga-Hee Shin Chan-Il Park Heebal Kim Woori Kwak Biotechnology Research Division National Institute of Fisheries Science Busan 46083 Republic of Korea. Interdisciplinary Program in Bioinformatics Seoul National University Seoul Republic of Korea. Research and Development Center Insilicogen Inc. Gyeonggi-do 16954 Republic of Korea. Department of Marine Biology & Aquaculture Gyeongsang National University Tongyeong 53064 Republic of Korea. C&K genomics 26 Beobwon-ro 9-gil H business Park Bldg. C #1008 Songpa-gu Seoul Republic of Korea. Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences 7 Seoul National University Seoul Republic of Korea. C&K genomics 26 Beobwon-ro 9-gil H business Park Bldg. C #1008 Songpa-gu Seoul Republic of Korea. asleo@***.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

关键词：

来源：评论

学校读者我要写书评

暂无评论

Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution (vol 33, pg 568, 2020)

引用

NATURE GENETICS 2020年第4期52卷 463-463页

作者： Chan-Seng-Yue, Michelle Kim, Jaeseung C. Wilson, Gavin W. Ng, Karen Figueroa, Eugenia Flores O'Kane, Grainne M. Connor, Ashton A. Denroche, Robert E. Grant, Robert C. McLeod, Jessica Wilson, Julie M. Jang, Gun Ho Zhang, Amy Liang, Sheng-Ben Borgida, Ayelet Chadwick, Dianne Kalimuthu, Sangeetha Lungu, Ilinca Bartlett, John M. S. Krzyzanowski, Paul M. Sandhu, Vandana Tiriac, Herve Froeling, Fieke E. M. Karasinska, Joanna M. Topham, James T. Renouf, Daniel J. Schaeffer, David F. Jones, Steven J. M. Marra, Marco A. Laskin, Janessa Chetty, Runjan Stein, Lincoln D. Zogopoulos, George Haibe-Kains, Benjamin Campbell, Peter J. Tuveson, David A. Knox, Jennifer J. Fischer, Sandra E. Gallinger, Steven Notta, Faiyaz Princess Margaret Cancer Centre Toronto Ontario Canada PanCuRx Translational Research Initiative Ontario Institute for Cancer Research Toronto Ontario Canada Genomics Technology Program Ontario Institute for Cancer Research Toronto Ontario Canada Wallace McCain Centre for Pancreatic Cancer Department of Medical Oncology Princess Margaret Centre University Health Network University of Toronto Toronto Ontario Canada Hepatobiliary/Pancreatic Surgical Oncology Program University Health Network Toronto Ontario Canada UHN Program in BioSpecimen Sciences University Health Network Toronto Ontario Canada Lunenfeld-Tanenbaum Research Institute Mount Sinai Hospital Toronto Ontario Canada Department of Pathology University Health Network and University of Toronto Toronto Ontario Canada Diagnostic Development Ontario Institute for Cancer Research Toronto Ontario Canada Cold Spring Harbor Laboratory Cold Spring Harbor NY USA Lustgarten Foundation Pancreatic Cancer Research Laboratory Cold Spring Harbor NY USA Department of Surgery and Cancer Imperial College London London UK Pancreas Centre BC Vancouver British Columbia Canada Department of Medical Oncology BC Cancer Vancouver British Columbia Canada Department of Pathology and Laboratory Medicine Vancouver General Hospital Vancouver British Columbia Canada Canada’s Michael Smith Genome Sciences Centre Vancouver British Columbia Canada Department of Medical Genetics University of British Columbia Vancouver British Columbia Canada Bioinformatics Ontario Institute for Cancer Research Toronto Ontario Canada Department of Molecular Genetics University of Toronto Toronto Ontario Canada Research Institute of the McGill University Health Centre Montreal Quebec Canada The Goodman Cancer Research Centre of McGill University Montreal Quebec Canada Department of Medical Biophysics University of Toronto Toronto Ontario Canada Department of Computer Science University of Toronto Toronto Ontario Canada Can

Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression.

关键词： Pancreatic cancer Transcriptomics

来源：评论

学校读者我要写书评

暂无评论

Evaluating drug targets through human loss-of-function genetic variation (vol 581, pg 459, 2020)

引用

NATURE 2021年第7846期590卷 E56-E56页

作者： Minikel, Eric Vallabh Karczewski, Konrad J. Martin, Hilary C. Cummings, Beryl B. Whiffin, Nicola Rhodes, Daniel Alfoldi, Jessica Trembath, Richard C. van Heel, David A. Daly, Mark J. Schreiber, Stuart L. MacArthur, Daniel G. Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge MA USA Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge MA USA Chemical Biology and Therapeutics Science Program Broad Institute of MIT and Harvard Cambridge MA USA Analytical and Translational Genetics Unit Massachusetts General Hospital Boston MA USA Program in Biological and Biomedical Sciences Harvard Medical School Boston MA USA Henry and Allison McCance Center for Brain Health Massachusetts General Hospital Boston MA USA Department of Neurology Massachusetts General Hospital Boston MA USA Prion Alliance Cambridge MA USA National Heart and Lung Institute and MRC London Institute of Medical Sciences Imperial College London London UK National Heart & Lung Institute and MRC London Institute of Medical Sciences Imperial College London London UK Cardiovascular Research Centre Royal Brompton & Harefield Hospitals NHS Trust London UK European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton Cambridge UK Center for Genomic Medicine Massachusetts General Hospital Boston MA USA Program in Bioinformatics and Integrative Genomics Harvard Medical School Boston MA USA Broad Genomics Broad Institute of MIT and Harvard Cambridge MA USA Division of Genetics and Genomics Boston Children’s Hospital Boston MA USA Department of Pediatrics Harvard Medical School Boston MA USA Cardiac Arrhythmia Service and Cardiovascular Research Center Massachusetts General Hospital Boston MA USA Estonian Genome Center Institute of Genomics University of Tartu Tartu Estonia Department of Medicine Harvard Medical School Boston MA USA Cardiac Arrhythmia Service Massachusetts General Hospital Boston MA USA Centre for Population Genomics Garvan Institute of Medical Research and UNSW Sydney Sydney Australia Centre for Population Genomics Murdoch Children’s Research Institute Melbourne Australia Divi

来源：评论

学校读者我要写书评

暂无评论

Author Correction: The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics

npj biodiversity

引用

npj biodiversity 2024年第1期3卷 31页

作者： Ann M Mc Cartney Giulio Formenti Alice Mouton Diego De Panis Luísa S Marins Henrique G Leitão Genevieve Diedericks Joseph Kirangwa Marco Morselli Judit Salces-Ortiz Nuria Escudero Alessio Iannucci Chiara Natali Hannes Svardal Rosa Fernández Tim De Pooter Geert Joris Mojca Strazisar Jonathan M D Wood Katie E Herron Ole Seehausen Phillip C Watts Felix Shaw Robert P Davey Alice Minotto José M Fernández Astrid Böhne Carla Alegria Tyler Alioto Paulo C Alves Isabel R Amorim Jean-Marc Aury Niclas Backstrom Petr Baldrian Laima Baltrunaite Endre Barta Bertrand BedHom Caroline Belser Johannes Bergsten Laurie Bertrand Helena Bilandija Mahesh Binzer-Panchal Iliana Bista Mark Blaxter Paulo A V Borges Guilherme Borges Dias Mirte Bosse Tom Brown Rémy Bruggmann Elena Buena-Atienza Josephine Burgin Elena Buzan Alessia Cariani Nicolas Casadei Matteo Chiara Sergio Chozas Fedor Čiampor Angelica Crottini Corinne Cruaud Fernando Cruz Love Dalen Alessio De Biase Javier Del Campo Teo Delic Alice B Dennis Martijn F L Derks Maria Angela Diroma Mihajla Djan Simone Duprat Klara Eleftheriadi Philine G D Feulner Jean-François Flot Giobbe Forni Bruno Fosso Pascal Fournier Christine Fournier-Chambrillon Toni Gabaldon Shilpa Garg Carmela Gissi Luca Giupponi Jessica Gomez-Garrido Josefa González Miguel L Grilo Björn Grüning Thomas Guerin Nadege Guiglielmoni Marta Gut Marcel P Haesler Christoph Hahn Balint Halpern Peter W Harrison Julia Heintz Maris Hindrikson Jacob Höglund Kerstin Howe Graham M Hughes Benjamin Istace Mark J Cock Franc Janžekovič Zophonias O Jonsson Sagane Joye-Dind Janne J Koskimäki Boris Krystufek Justyna Kubacka Heiner Kuhl Szilvia Kusza Karine Labadie Meri Lähteenaro Henrik Lantz Anton Lavrinienko Lucas Leclère Ricardo Jorge Lopes Ole Madsen Ghislaine Magdelenat Giulia Magoga Tereza Manousaki Tapio Mappes Joao Pedro Marques Gemma I Martinez Redondo Florian Maumus Shane A McCarthy Hendrik-Jan Megens Jose Melo-Ferreira Sofia L Mendes Matteo Montagna Joao Moreno Mai-Britt Mosbech Mónica Moura Zuzana Musilova Eugene Myers Will J N Genomics Institute University of California Santa Cruz CA USA. anmmccar@ucsc.edu. The Vertebrate Genome Laboratory The Rockefeller University New York NY USA. Department of Biology University of Florence Sesto Fiorentino Italy. InBios-Conservation Genetics Laboratory University of Liege Liege Belgium. Leibniz Institut für Zoo und Wildtierforschung Berlin Germany. Berlin Center for Genomics in Biodiversity Research Berlin Germany. Department of Biology University of Antwerp Antwerp Belgium. Institute of Zoology University of Cologne Cologne Germany. Department of Chemistry Life Sciences and Environmental Sustainability University of Parma Parma Italy. Institute of Evolutionary Biology (CSIC-Universitat Pompeu Fabra) Barcelona Spain. Naturalis Biodiversity Center Leiden The Netherlands. Neuromics Support Facility VIB Center for Molecular Neurology VIB Antwerp Belgium. Neuromics Support Facility Department of Biomedical Sciences University of Antwerp Antwerp Belgium. Tree of Life Wellcome Sanger Institute Hinxton Cambridge UK. School of Biology and Environmental Science University College Dublin Belfield Ireland. Aquatic Ecology & Evolution Institute of Ecology & Evolution University of Bern Bern Switzerland. Department of Fish Ecology & Evolution Eawag Kastanienbaum Switzerland. Department of Biological and Environmental Science University of Jyvaskyla Jyvaskyla Finland. The Earlham Institute Norwich Research Park Norwich UK. Digital Science London UK. Barcelona Supercomputing Center Spanish National Bioinformatics Institute ELIXIR Spain Getafe Spain. Leibniz Institute for the Analysis of Biodiversity Change Museum Koenig Bonn Bonn Germany. CE3C-Centre for Ecology Evolution and Environmental Changes & CHANGE-Global Change and Sustainability Institute Faculdade de Ciências Universidade de Lisboa Campo Grande Lisboa Portugal. Centro Nacional de Análisis Genómico (CNAG) Barcelona Spain. Universitat de Barcelona (UB) Barcelona Spain. CIBIO C

来源：评论

学校读者我要写书评

暂无评论

A Bayesian mixture model for clustering on the stiefel manifold

arXiv

引用

arXiv 2017年

作者： Sengupta, Subhajit Pal, Subhadip Mitra, Riten Guo, Ying Banerjee, Arunava Ji, Yuan Program for Computational Genomics and Medicine NorthShore University HealthSystem Department of Bioinformatics and Biostatistics University of Louisville Department of Biostatistics and Bioinformatics Emory University Department of Computer and Information Science and Engineering University of Florida Department of Public Health Sciences University of Chicago

Analysis of a Bayesian mixture model for the Matrix Langevin distribution on the Stiefel manifold is presented. The model exploits a particular parametrization of the Matrix Langevin distribution, various aspects of which are elaborated on. A general, and novel, family of conjugate priors, and an efficient Markov chain Monte Carlo (MCMC) sampling scheme for the corresponding posteriors is then developed for the mixture model. Theoretical properties of the prior and posterior distributions, including posterior consistency, are explored in detail. Extensive simulation experiments are presented to validate the efficacy of the framework. Real-world examples, including a large scale neuroimaging dataset, are analyzed to demonstrate the computational tractability of the approach. Copyright © 2017, The Authors. All rights reserved.

关键词： Mixtures

来源：评论

学校读者我要写书评

暂无评论

Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021)

引用

EUROPEAN JOURNAL OF HUMAN GENETICS 2022年第5期30卷 630-631页

作者： Dareng, Eileen O. Tyrer, Jonathan P. Barnes, Daniel R. Jones, Michelle R. Yang, Xin Aben, Katja K. H. Adank, Muriel A. Agata, Simona Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Aravantinos, Gerasimos Arun, Banu K. Augustinsson, Annelie Balmana, Judith Bandera, Elisa V. Barkardottir, Rosa B. Barrowdale, Daniel Beckmann, Matthias W. Beeghly-Fadiel, Alicia Benitez, Javier Bermisheva, Marina Bernardini, Marcus Q. Bjorge, Line Black, Amanda Bogdanova, Natalia V. Bonanni, Bernardo Borg, Ake Brenton, James D. Budzilowska, Agnieszka Butzow, Ralf Buys, Saundra S. Cai, Hui Caligo, Maria A. Campbell, Ian Cannioto, Rikki Cassingham, Hayley Chang-Claude, Jenny Chanock, Stephen J. Chen, Kexin Chiew, Yoke-Eng Chung, Wendy K. Claes, Kathleen B. M. Colonna, Sarah Cook, Linda S. Couch, Fergus J. Daly, Mary B. Dao, Fanny Davies, Eleanor de la Hoya, Miguel de Putter, Robin Dennis, Joe DePersia, Allison Devilee, Peter Diez, Orland Ding, Yuan Chun Doherty, Jennifer A. Domchek, Susan M. Dork, Thilo du Bois, Andreas Durst, Matthias Eccles, Diana M. Eliassen, Heather A. Engel, Christoph Evans, Gareth D. Fasching, Peter A. Flanagan, James M. Fortner, Renee T. Machackova, Eva Friedman, Eitan Ganz, Patricia A. Garber, Judy Gensini, Francesca Giles, Graham G. Glendon, Gord Godwin, Andrew K. Goodman, Marc T. Greene, Mark H. Gronwald, Jacek Hahnen, Eric Haiman, Christopher A. Hakansson, Niclas Hamann, Ute Hansen, Thomas V. O. Harris, Holly R. Hartman, Mikael Heitz, Florian Hildebrandt, Michelle A. T. Hogdall, Estrid Hogdall, Claus K. Hopper, John L. Huang, Ruea-Yea Huff, Chad Hulick, Peter J. Huntsman, David G. Imyanitov, Evgeny N. Isaacs, Claudine Jakubowska, Anna James, Paul A. Janavicius, Ramunas Jensen, Allan Johannsson, Oskar Th. John, Esther M. Jones, Michael E. Kang, Daehee Karlan, Beth Y. Karnezis, Anthony Kelemen, Linda E. Khusnutdinova, Elza Kiemeney, Lambertus A. Kim, Byoung-Gie Kjaer, Susanne K. Komenaka, Ian Kupryjanczyk, Jolanta Kurian, Allison W. Kwong, Ava Lambrechts, Diether Larson, Melissa C. Lazaro, Conxi L 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 Epidemiology Department

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

关键词： Clinical genetics Genetic markers Risk factors Biomedicine general Human Genetics bioinformatics Gene Expression Cytogenetics

来源：评论

学校读者我要写书评

暂无评论

Africa-specific human genetic variation near CHD1L associates with HIV-1 load (vol 620, pg 1025, 2023)

引用

NATURE 2023年第7979期621卷 E42-E42页

作者： McLaren, Paul J. Porreca, Immacolata Iaconis, Gennaro Mok, Hoi Ping Mukhopadhyay, Subhankar Karakoc, Emre Cristinelli, Sara Pomilla, Cristina Bartha, Istvan Thorball, Christian W. Tough, Riley H. Angelino, Paolo Kiar, Cher S. Carstensen, Tommy Fatumo, Segun Porter, Tarryn Jarvis, Isobel Skarnes, William C. Bassett, Andrew DeGorter, Marianne K. Moorthy, Mohana Prasad Sathya Tuff, Jeffrey F. Kim, Eun-Young Walter, Miriam Simons, Lacy M. Bashirova, Arman Buchbinder, Susan Carrington, Mary Cossarizza, Andrea De Luca, Andrea Goedert, James J. Goldstein, David B. Haas, David W. Herbeck, Joshua T. Johnson, Eric O. Kaleebu, Pontiano Kilembe, William Kirk, Gregory D. Kootstra, Neeltje A. Kral, Alex H. Lambotte, Olivier Luo, Ma Mallal, Simon Martinez-Picado, Javier Meyer, Laurence Miro, Jose M. Moodley, Pravi Motala, Ayesha A. Mullins, James I. Nam, Kireem Obel, Niels Pirie, Fraser Plummer, Francis A. Poli, Guido Price, Matthew A. Rauch, Andri Theodorou, Ioannis Trkola, Alexandra Walker, Bruce D. Winkler, Cheryl A. Zagury, Jean-Francois Montgomery, Stephen B. Ciuffi, Angela Hultquist, Judd F. Wolinsky, Steven M. Dougan, Gordon Lever, Andrew M. L. Gurdasani, Deepti Groom, Harriet Sandhu, Manjinder S. Fellay, Jacques Sexually Transmitted and Blood-Borne Infections Division at JC Wilt Infectious Diseases Research Centre National Microbiology Laboratory Branch Public Health Agency of Canada Winnipeg Manitoba Canada Department of Medical Microbiology and Infectious Diseases University of Manitoba Winnipeg Manitoba Canada Vaccine and Therapeutics Laboratory Medical and Scientific Affairs National Microbiology Laboratory Branch Public Health Agency of Canada Winnipeg Manitoba Canada Wellcome Trust Sanger Institute Hinxton UK Department of Medicine University of Cambridge Cambridge UK Department of Medicine National University of Singapore Singapore Singapore Peter Gorer Department of Immunobiology School of Immunology and Microbial Sciences King’s College London London UK Institute of Microbiology Lausanne University Hospital and University of Lausanne Lausanne Switzerland Global Health Institute School of Life Sciences École Polytechnique Fédérale de Lausanne Lausanne Switzerland Swiss Institute of Bioinformatics Lausanne Switzerland Precision Medicine Unit Biomedical Data Science Center Lausanne University Hospital (CHUV) and University of Lausanne Lausanne Switzerland The African Computational Genomics (TACG) Research Group MRC/UVRI and LSHTM Uganda Research Unit Entebbe Uganda Department of Non-Communicable Disease Epidemiology Faculty of Epidemiology and Population Health London School of Hygiene and Tropical Medicine London UK The Jackson Laboratory for Genomic Medicine Farmington CT USA Department of Pathology Stanford University School of Medicine Stanford CA USA Department of Genetics Stanford University School of Medicine Stanford CA USA Division of Infectious Diseases Feinberg School of Medicine Northwestern University Chicago IL USA Basic Science Program Frederick National Laboratory for Cancer Research National Cancer Institute Frederick MD USA Laboratory of Integrative Cancer Immunology Center for Cancer Research National Cancer Institute Bethesda

来源：评论

学校读者我要写书评

暂无评论

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案：

请选择收藏分类：

通借通还

建议与咨询 留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案： 新增检索档案 确定 取消

请选择收藏分类： 新增自定义分类 确定 取消

通借通还

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

请选择保存的检索档案：

请选择收藏分类：