PURPOSE: The high attrition rate of cancer drug development programs is a barrier to realizing the promise of precision oncology. We have examined whether the genetic insights from genome-wide association studies of cancer can guide drug development and repurposing in oncology. MATERIALS AND METHODS: Across 37 cancers, we identified 955 genetic risk variants from the National Human Genome Research Institute-European Bioinformatics Institute genome-wide association study catalog. We linked these variants to target genes using strategies that were based on linkage disequilibrium, DNA three-dimensional structure, and integration of predicted gene function and expression. With the use of the Informa Pharmaprojects database, we identified genes that are targets of unique drugs and assessed the level of enrichment that would be afforded by incorporation of genetic information in preclinical and phase II studies. For targets not under development, we implemented machine learning approaches to assess druggability. RESULTS: For all preclinical targets incorporating genetic information, a 2.00-fold enrichment of a drug being successfully approved could be achieved (95% CI, 1.14- to 3.48-fold; P = .02). For phase II targets, a 2.75-fold enrichment could be achieved (95% CI, 1.42- to 5.35-fold; P < .001). Application of genetic information suggests potential repurposing of 15 approved nononcology drugs. CONCLUSION: The findings illustrate the value of using insights from the genetics of inherited cancer susceptibility discovery projects as part of a data-driven strategy to inform drug discovery. Support for cancer germline genetic information for prospective targets is available online from the Institute of Cancer Research.
PURPOSE: The high attrition rate of cancer drug development programs is a barrier to realizing the promise of precision oncology. We have examined whether the genetic insights from genome-wide association studies of cancer can guide drug development and repurposing in oncology. MATERIALS AND METHODS: Across 37 cancers, we identified 955 genetic risk variants from the National Human Genome Research Institute-European Bioinformatics Institute genome-wide association study catalog. We linked these variants to target genes using strategies that were based on linkage disequilibrium, DNA three-dimensional structure, and integration of predicted gene function and expression. With the use of the Informa Pharmaprojects database, we identified genes that are targets of unique drugs and assessed the level of enrichment that would be afforded by incorporation of genetic information in preclinical and phase II studies. For targets not under development, we implemented machine learning approaches to assess druggability. RESULTS: For all preclinical targets incorporating genetic information, a 2.00-fold enrichment of a drug being successfully approved could be achieved (95% CI, 1.14- to 3.48-fold; P = .02). For phase II targets, a 2.75-fold enrichment could be achieved (95% CI, 1.42- to 5.35-fold; P < .001). Application of genetic information suggests potential repurposing of 15 approved nononcology drugs. CONCLUSION: The findings illustrate the value of using insights from the genetics of inherited cancer susceptibility discovery projects as part of a data-driven strategy to inform drug discovery. Support for cancer germline genetic information for prospective targets is available online from the Institute of Cancer Research.
Authors: Maria Chiara Di Bernardo; Dalemari Crowther-Swanepoel; Peter Broderick; Emily Webb; Gabrielle Sellick; Ruth Wild; Kate Sullivan; Jayaram Vijayakrishnan; Yufei Wang; Alan M Pittman; Nicola J Sunter; Andrew G Hall; Martin J S Dyer; Estella Matutes; Claire Dearden; Tryfonia Mainou-Fowler; Graham H Jackson; Geoffrey Summerfield; Robert J Harris; Andrew R Pettitt; Peter Hillmen; David J Allsup; James R Bailey; Guy Pratt; Chris Pepper; Chris Fegan; James M Allan; Daniel Catovsky; Richard S Houlston Journal: Nat Genet Date: 2008-08-31 Impact factor: 38.330
Authors: Christopher I Amos; Xifeng Wu; Peter Broderick; Ivan P Gorlov; Jian Gu; Timothy Eisen; Qiong Dong; Qing Zhang; Xiangjun Gu; Jayaram Vijayakrishnan; Kate Sullivan; Athena Matakidou; Yufei Wang; Gordon Mills; Kimberly Doheny; Ya-Yu Tsai; Wei Vivien Chen; Sanjay Shete; Margaret R Spitz; Richard S Houlston Journal: Nat Genet Date: 2008-04-02 Impact factor: 38.330
Authors: Fiona Taylor; Mark D Huffman; Ana Filipa Macedo; Theresa H M Moore; Margaret Burke; George Davey Smith; Kirsten Ward; Shah Ebrahim Journal: Cochrane Database Syst Rev Date: 2013-01-31
Authors: P Andrew Futreal; Lachlan Coin; Mhairi Marshall; Thomas Down; Timothy Hubbard; Richard Wooster; Nazneen Rahman; Michael R Stratton Journal: Nat Rev Cancer Date: 2004-03 Impact factor: 60.716
Authors: Brian G Feagan; William J Sandborn; Christopher Gasink; Douglas Jacobstein; Yinghua Lang; Joshua R Friedman; Marion A Blank; Jewel Johanns; Long-Long Gao; Ye Miao; Omoniyi J Adedokun; Bruce E Sands; Stephen B Hanauer; Severine Vermeire; Stephan Targan; Subrata Ghosh; Willem J de Villiers; Jean-Frédéric Colombel; Zsolt Tulassay; Ursula Seidler; Bruce A Salzberg; Pierre Desreumaux; Scott D Lee; Edward V Loftus; Levinus A Dieleman; Seymour Katz; Paul Rutgeerts Journal: N Engl J Med Date: 2016-11-17 Impact factor: 91.245
Authors: Chris Finan; Anna Gaulton; Felix A Kruger; R Thomas Lumbers; Tina Shah; Jorgen Engmann; Luana Galver; Ryan Kelley; Anneli Karlsson; Rita Santos; John P Overington; Aroon D Hingorani; Juan P Casas Journal: Sci Transl Med Date: 2017-03-29 Impact factor: 17.956
Authors: Karim Labreche; Ben Kinnersley; Giulia Berzero; Anna Luisa Di Stefano; Amithys Rahimian; Ines Detrait; Yannick Marie; Benjamin Grenier-Boley; Khe Hoang-Xuan; Jean-Yves Delattre; Ahmed Idbaih; Richard S Houlston; Marc Sanson Journal: Acta Neuropathol Date: 2018-02-19 Impact factor: 17.088
Authors: Roger L Milne; Karoline B Kuchenbaecker; Kyriaki Michailidou; Jonathan Beesley; Siddhartha Kar; Sara Lindström; Shirley Hui; Audrey Lemaçon; Penny Soucy; Joe Dennis; Xia Jiang; Asha Rostamianfar; Hilary Finucane; Manjeet K Bolla; Lesley McGuffog; Qin Wang; Cora M Aalfs; Marcia Adams; Julian Adlard; Simona Agata; Shahana Ahmed; Habibul Ahsan; Kristiina Aittomäki; Fares Al-Ejeh; Jamie Allen; Christine B Ambrosone; Christopher I Amos; Irene L Andrulis; Hoda Anton-Culver; Natalia N Antonenkova; Volker Arndt; Norbert Arnold; Kristan J Aronson; Bernd Auber; Paul L Auer; Margreet G E M Ausems; Jacopo Azzollini; François Bacot; Judith Balmaña; Monica Barile; Laure Barjhoux; Rosa B Barkardottir; Myrto Barrdahl; Daniel Barnes; Daniel Barrowdale; Caroline Baynes; Matthias W Beckmann; Javier Benitez; Marina Bermisheva; Leslie Bernstein; Yves-Jean Bignon; Kathleen R Blazer; Marinus J Blok; Carl Blomqvist; William Blot; Kristie Bobolis; Bram Boeckx; Natalia V Bogdanova; Anders Bojesen; Stig E Bojesen; Bernardo Bonanni; Anne-Lise Børresen-Dale; Aniko Bozsik; Angela R Bradbury; Judith S Brand; Hiltrud Brauch; Hermann Brenner; Brigitte Bressac-de Paillerets; Carole Brewer; Louise Brinton; Per Broberg; Angela Brooks-Wilson; Joan Brunet; Thomas Brüning; Barbara Burwinkel; Saundra S Buys; Jinyoung Byun; Qiuyin Cai; Trinidad Caldés; Maria A Caligo; Ian Campbell; Federico Canzian; Olivier Caron; Angel Carracedo; Brian D Carter; J Esteban Castelao; Laurent Castera; Virginie Caux-Moncoutier; Salina B Chan; Jenny Chang-Claude; Stephen J Chanock; Xiaoqing Chen; Ting-Yuan David Cheng; Jocelyne Chiquette; Hans Christiansen; Kathleen B M Claes; Christine L Clarke; Thomas Conner; Don M Conroy; Jackie Cook; Emilie Cordina-Duverger; Sten Cornelissen; Isabelle Coupier; Angela Cox; David G Cox; Simon S Cross; Katarina Cuk; Julie M Cunningham; Kamila Czene; Mary B Daly; Francesca Damiola; Hatef Darabi; Rosemarie Davidson; Kim De Leeneer; Peter Devilee; Ed Dicks; Orland Diez; Yuan Chun Ding; Nina Ditsch; Kimberly F Doheny; Susan M Domchek; Cecilia M Dorfling; Thilo Dörk; Isabel Dos-Santos-Silva; Stéphane Dubois; Pierre-Antoine Dugué; Martine Dumont; Alison M Dunning; Lorraine Durcan; Miriam Dwek; Bernd Dworniczak; Diana Eccles; Ros Eeles; Hans Ehrencrona; Ursula Eilber; Bent Ejlertsen; Arif B Ekici; A Heather Eliassen; Christoph Engel; Mikael Eriksson; Laura Fachal; Laurence Faivre; Peter A Fasching; Ulrike Faust; Jonine Figueroa; Dieter Flesch-Janys; Olivia Fletcher; Henrik Flyger; William D Foulkes; Eitan Friedman; Lin Fritschi; Debra Frost; Marike Gabrielson; Pragna Gaddam; Marilie D Gammon; Patricia A Ganz; Susan M Gapstur; Judy Garber; Vanesa Garcia-Barberan; José A García-Sáenz; Mia M Gaudet; Marion Gauthier-Villars; Andrea Gehrig; Vassilios Georgoulias; Anne-Marie Gerdes; Graham G Giles; Gord Glendon; Andrew K Godwin; Mark S Goldberg; David E Goldgar; Anna González-Neira; Paul Goodfellow; Mark H Greene; Grethe I Grenaker Alnæs; Mervi Grip; Jacek Gronwald; Anne Grundy; Daphne Gschwantler-Kaulich; Pascal Guénel; Qi Guo; Lothar Haeberle; Eric Hahnen; Christopher A Haiman; Niclas Håkansson; Emily Hallberg; Ute Hamann; Nathalie Hamel; Susan Hankinson; Thomas V O Hansen; Patricia Harrington; Steven N Hart; Jaana M Hartikainen; Catherine S Healey; Alexander Hein; Sonja Helbig; Alex Henderson; Jane Heyworth; Belynda Hicks; Peter Hillemanns; Shirley Hodgson; Frans B Hogervorst; Antoinette Hollestelle; Maartje J Hooning; Bob Hoover; John L Hopper; Chunling Hu; Guanmengqian Huang; Peter J Hulick; Keith Humphreys; David J Hunter; Evgeny N Imyanitov; Claudine Isaacs; Motoki Iwasaki; Louise Izatt; Anna Jakubowska; Paul James; Ramunas Janavicius; Wolfgang Janni; Uffe Birk Jensen; Esther M John; Nichola Johnson; Kristine Jones; Michael Jones; Arja Jukkola-Vuorinen; Rudolf Kaaks; Maria Kabisch; Katarzyna Kaczmarek; Daehee Kang; Karin Kast; Renske Keeman; Michael J Kerin; Carolien M Kets; Machteld Keupers; Sofia Khan; Elza Khusnutdinova; Johanna I Kiiski; Sung-Won Kim; Julia A Knight; Irene Konstantopoulou; Veli-Matti Kosma; Vessela N Kristensen; Torben A Kruse; Ava Kwong; Anne-Vibeke Lænkholm; Yael Laitman; Fiona Lalloo; Diether Lambrechts; Keren Landsman; Christine Lasset; Conxi Lazaro; Loic Le Marchand; Julie Lecarpentier; Andrew Lee; Eunjung Lee; Jong Won Lee; Min Hyuk Lee; Flavio Lejbkowicz; Fabienne Lesueur; Jingmei Li; Jenna Lilyquist; Anne Lincoln; Annika Lindblom; Jolanta Lissowska; Wing-Yee Lo; Sibylle Loibl; Jirong Long; Jennifer T Loud; Jan Lubinski; Craig Luccarini; Michael Lush; Robert J MacInnis; Tom Maishman; Enes Makalic; Ivana Maleva Kostovska; Kathleen E Malone; Siranoush Manoukian; JoAnn E Manson; Sara Margolin; John W M Martens; Maria Elena Martinez; Keitaro Matsuo; Dimitrios Mavroudis; Sylvie Mazoyer; Catriona McLean; Hanne Meijers-Heijboer; Primitiva Menéndez; Jeffery Meyer; Hui Miao; Austin Miller; Nicola Miller; Gillian Mitchell; Marco Montagna; Kenneth Muir; Anna Marie Mulligan; Claire Mulot; Sue Nadesan; Katherine L Nathanson; Susan L Neuhausen; Heli Nevanlinna; Ines Nevelsteen; Dieter Niederacher; Sune F Nielsen; Børge G Nordestgaard; Aaron Norman; Robert L Nussbaum; Edith Olah; Olufunmilayo I Olopade; Janet E Olson; Curtis Olswold; Kai-Ren Ong; Jan C Oosterwijk; Nick Orr; Ana Osorio; V Shane Pankratz; Laura Papi; Tjoung-Won Park-Simon; Ylva Paulsson-Karlsson; Rachel Lloyd; Inge Søkilde Pedersen; Bernard Peissel; Ana Peixoto; Jose I A Perez; Paolo Peterlongo; Julian Peto; Georg Pfeiler; Catherine M Phelan; Mila Pinchev; Dijana Plaseska-Karanfilska; Bruce Poppe; Mary E Porteous; Ross Prentice; Nadege Presneau; Darya Prokofieva; Elizabeth Pugh; Miquel Angel Pujana; Katri Pylkäs; Brigitte Rack; Paolo Radice; Nazneen Rahman; Johanna Rantala; Christine Rappaport-Fuerhauser; Gad Rennert; Hedy S Rennert; Valerie Rhenius; Kerstin Rhiem; Andrea Richardson; Gustavo C Rodriguez; Atocha Romero; Jane Romm; Matti A Rookus; Anja Rudolph; Thomas Ruediger; Emmanouil Saloustros; Joyce Sanders; Dale P Sandler; Suleeporn Sangrajrang; Elinor J Sawyer; Daniel F Schmidt; Minouk J Schoemaker; Fredrick Schumacher; Peter Schürmann; Lukas Schwentner; Christopher Scott; Rodney J Scott; Sheila Seal; Leigha Senter; Caroline Seynaeve; Mitul Shah; Priyanka Sharma; Chen-Yang Shen; Xin Sheng; Hermela Shimelis; Martha J Shrubsole; Xiao-Ou Shu; Lucy E Side; Christian F Singer; Christof Sohn; Melissa C Southey; John J Spinelli; Amanda B Spurdle; Christa Stegmaier; Dominique Stoppa-Lyonnet; Grzegorz Sukiennicki; Harald Surowy; Christian Sutter; Anthony Swerdlow; Csilla I Szabo; Rulla M Tamimi; Yen Y Tan; Jack A Taylor; Maria-Isabel Tejada; Maria Tengström; Soo H Teo; Mary B Terry; Daniel C Tessier; Alex Teulé; Kathrin Thöne; Darcy L Thull; Maria Grazia Tibiletti; Laima Tihomirova; Marc Tischkowitz; Amanda E Toland; Rob A E M Tollenaar; Ian Tomlinson; Ling Tong; Diana Torres; Martine Tranchant; Thérèse Truong; Kathy Tucker; Nadine Tung; Jonathan Tyrer; Hans-Ulrich Ulmer; Celine Vachon; Christi J van Asperen; David Van Den Berg; Ans M W van den Ouweland; Elizabeth J van Rensburg; Liliana Varesco; Raymonda Varon-Mateeva; Ana Vega; Alessandra Viel; Joseph Vijai; Daniel Vincent; Jason Vollenweider; Lisa Walker; Zhaoming Wang; Shan Wang-Gohrke; Barbara Wappenschmidt; Clarice R Weinberg; Jeffrey N Weitzel; Camilla Wendt; Jelle Wesseling; Alice S Whittemore; Juul T Wijnen; Walter Willett; Robert Winqvist; Alicja Wolk; Anna H Wu; Lucy Xia; Xiaohong R Yang; Drakoulis Yannoukakos; Daniela Zaffaroni; Wei Zheng; Bin Zhu; Argyrios Ziogas; Elad Ziv; Kristin K Zorn; Manuela Gago-Dominguez; Arto Mannermaa; Håkan Olsson; Manuel R Teixeira; Jennifer Stone; Kenneth Offit; Laura Ottini; Sue K Park; Mads Thomassen; Per Hall; Alfons Meindl; Rita K Schmutzler; Arnaud Droit; Gary D Bader; Paul D P Pharoah; Fergus J Couch; Douglas F Easton; Peter Kraft; Georgia Chenevix-Trench; Montserrat García-Closas; Marjanka K Schmidt; Antonis C Antoniou; Jacques Simard Journal: Nat Genet Date: 2017-10-23 Impact factor: 38.330
Authors: Rita Santos; Oleg Ursu; Anna Gaulton; A Patrícia Bento; Ramesh S Donadi; Cristian G Bologa; Anneli Karlsson; Bissan Al-Lazikani; Anne Hersey; Tudor I Oprea; John P Overington Journal: Nat Rev Drug Discov Date: 2016-12-02 Impact factor: 84.694
Authors: Ali Amin Al Olama; Zsofia Kote-Jarai; Sonja I Berndt; David V Conti; Fredrick Schumacher; Ying Han; Sara Benlloch; Dennis J Hazelett; Zhaoming Wang; Ed Saunders; Daniel Leongamornlert; Sara Lindstrom; Sara Jugurnauth-Little; Tokhir Dadaev; Malgorzata Tymrakiewicz; Daniel O Stram; Kristin Rand; Peggy Wan; Alex Stram; Xin Sheng; Loreall C Pooler; Karen Park; Lucy Xia; Jonathan Tyrer; Laurence N Kolonel; Loic Le Marchand; Robert N Hoover; Mitchell J Machiela; Merideth Yeager; Laurie Burdette; Charles C Chung; Amy Hutchinson; Kai Yu; Chee Goh; Mahbubl Ahmed; Koveela Govindasami; Michelle Guy; Teuvo L J Tammela; Anssi Auvinen; Tiina Wahlfors; Johanna Schleutker; Tapio Visakorpi; Katri A Leinonen; Jianfeng Xu; Markus Aly; Jenny Donovan; Ruth C Travis; Tim J Key; Afshan Siddiq; Federico Canzian; Kay-Tee Khaw; Atsushi Takahashi; Michiaki Kubo; Paul Pharoah; Nora Pashayan; Maren Weischer; Borge G Nordestgaard; Sune F Nielsen; Peter Klarskov; Martin Andreas Røder; Peter Iversen; Stephen N Thibodeau; Shannon K McDonnell; Daniel J Schaid; Janet L Stanford; Suzanne Kolb; Sarah Holt; Beatrice Knudsen; Antonio Hurtado Coll; Susan M Gapstur; W Ryan Diver; Victoria L Stevens; Christiane Maier; Manuel Luedeke; Kathleen Herkommer; Antje E Rinckleb; Sara S Strom; Curtis Pettaway; Edward D Yeboah; Yao Tettey; Richard B Biritwum; Andrew A Adjei; Evelyn Tay; Ann Truelove; Shelley Niwa; Anand P Chokkalingam; Lisa Cannon-Albright; Cezary Cybulski; Dominika Wokołorczyk; Wojciech Kluźniak; Jong Park; Thomas Sellers; Hui-Yi Lin; William B Isaacs; Alan W Partin; Hermann Brenner; Aida Karina Dieffenbach; Christa Stegmaier; Constance Chen; Edward L Giovannucci; Jing Ma; Meir Stampfer; Kathryn L Penney; Lorelei Mucci; Esther M John; Sue A Ingles; Rick A Kittles; Adam B Murphy; Hardev Pandha; Agnieszka Michael; Andrzej M Kierzek; William Blot; Lisa B Signorello; Wei Zheng; Demetrius Albanes; Jarmo Virtamo; Stephanie Weinstein; Barbara Nemesure; John Carpten; Cristina Leske; Suh-Yuh Wu; Anselm Hennis; Adam S Kibel; Benjamin A Rybicki; Christine Neslund-Dudas; Ann W Hsing; Lisa Chu; Phyllis J Goodman; Eric A Klein; S Lilly Zheng; Jyotsna Batra; Judith Clements; Amanda Spurdle; Manuel R Teixeira; Paula Paulo; Sofia Maia; Chavdar Slavov; Radka Kaneva; Vanio Mitev; John S Witte; Graham Casey; Elizabeth M Gillanders; Daniella Seminara; Elio Riboli; Freddie C Hamdy; Gerhard A Coetzee; Qiyuan Li; Matthew L Freedman; David J Hunter; Kenneth Muir; Henrik Gronberg; David E Neal; Melissa Southey; Graham G Giles; Gianluca Severi; Michael B Cook; Hidewaki Nakagawa; Fredrik Wiklund; Peter Kraft; Stephen J Chanock; Brian E Henderson; Douglas F Easton; Rosalind A Eeles; Christopher A Haiman Journal: Nat Genet Date: 2014-09-14 Impact factor: 38.330