Integrative pathway enrichment analysis of multivariate omics data
Marta Paczkowska, Jonathan Barenboim, Nardnisa Sintupisut, Natalie S. Fox, Helen Zhu, Diala Abd-Rabbo, Miles W. Mee, Paul C. Boutros, PCAWG Drivers and Functional Interpretation Working Group, Federico Abascal, Samirkumar B. Amin, Gary D. Bader, Rameen Beroukhim, Johanna Bertl, Keith A. Boroevich, Søren Brunak, Peter J. Campbell, Joana Carlevaro-Fita, Dimple Chakravarty, Calvin Wing Yiu Chan, Ken Chen, Jung Kyoon Choi, Jordi Deu-Pons, Priyanka Dhingra, Klev Diamanti, Lars Feuerbach, J. Lynn Fink, Nuno A. Fonseca, Joan Frigola, Carlo Gambacorti‐Passerini, Dale W. Garsed, Mark Gerstein, Gad Getz, Abel González-Pérez, Qianyun Guo, Marta Gut, David Haan, Mark Hamilton, Nicholas J. Haradhvala, Arif Harmanci, Mohamed Helmy, Carl Herrmann, Julian M. Hess, Asger Hobolth, Ermin Hodzic, Chen Hong, Henrik Hornshøj, Keren Isaev, José M. G. Izarzugaza, Rory Johnson, Todd A. Johnson, Malene Juul, Randi Istrup Juul, Andre Kahles, Abdullah Kahraman, Manolis Kellis, Ekta Khurana, Jaegil Kim, Jong K. Kim, Young-Wook Kim, Jan Komorowski, Jan O. Korbel, Sushant Kumar, Andrés Lanzós, Michael S. Lawrence, Shantao Li, Kjong-Van Lehmann, Shantao Li, Xiaotong Li, Ziao Lin, Eric Minwei Liu, Lucas Lochovsky, Shaoke Lou, Tobias Madsen, Kathleen Marchal, Iñigo Martincorena, Alexander Martinez‐Fundichely, Yosef E. Maruvka, Patrick D. McGillivray, William Meyerson, Ferran Muiños, Loris Mularoni, Hidewaki Nakagawa, Morten Muhlig Nielsen, Keunchil Park, Kiejung Park, Jakob Skou Pedersen, Oriol Pich, Tirso Pons, Sergio Pulido-Tamayo, Benjamin J. Raphael, Iker Reyes-Salazar, Matthew A. Reyna, Esther Rheinbay, Mark A. Rubin, Carlota Rubio-Pérez, Radhakrishnan Sabarinathan, S. Cenk Şahinalp, Gordon Saksena, Leonidas Salichos
Abstract
Multi-omics datasets represent distinct aspects of the central dogma of molecular biology. Such high-dimensional molecular profiles pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple datasets using statistical data fusion, rationalizes contributing evidence and highlights associated genes. As part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumor types, we integrated genes with coding and non-coding mutations and revealed frequently mutated pathways and additional cancer genes with infrequent mutations. We also analyzed prognostic molecular pathways by integrating genomic and transcriptomic features of 1780 breast cancers and highlighted associations with immune response and anti-apoptotic signaling. Integration of ChIP-seq and RNA-seq data for master regulators of the Hippo pathway across normal human tissues identified processes of tissue regeneration and stem cell regulation. ActivePathways is a versatile method that improves systems-level understanding of cellular organization in health and disease through integration of multiple molecular datasets and pathway annotations.