Dina ElHarouni, Mushriq Al-Jazrawe, Seongmin Choi, Merve Dede, Toshinori Hinoue, Sean A Misek, Heeju Noh, Luca Zanella, Yuen-Yi Tseng, Hayley E Francies, Dennis Plenker, Cindy W Kyi, Julyann Perez-Mayoral, Megan J Stine, Eva Tonsing-Carter, Rachana Agarwal, Jean Claude Zenklusen, James M Clinton, Jennifer M Shelton, Timothy R Chu, William F Hooper, Xavi Loinaz, Paula Keskula, Jordan Tagle, Peyton C Kuhlers, Bahar Tercan, Sylvia F Boj, Alessandro Vasciaveo, Lorenzo Tomassoni, James M Crawford, Shawna Walsh, Claire Sinai, Sonam Bhatia, Priya Sridevi, Hardik Patel, Maria Antonietta Cerone, HCMI Network, Kyle Ellrott, Calvin J Kuo, Olivier Elemento, Semir Beyaz, Vincenzo Corbo, David L Spector, Rameen Beroukhim, Martin L Ferguson, Andrew D Cherniack, Peter W Laird, Nicolas Robine, Andrew McPherson, Katherine A Hoadley, Mathew J Garnett, David A Tuveson, Andrea Califano, Paul T Spellman, Keith L Ligon, Daniela S Gerhard, Louis M Staudt, Jesse S Boehm
The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.