Rafael A Rosales1, Rodrigo D Drummond2, Renan Valieris2, Emmanuel Dias-Neto3,4, Israel T da Silva2,5. 1. Departamento de Computação e Matemática, Universidade de São Paulo, Ribeirão Preto, SP 14040-901, Brazil. 2. Laboratory of Bioinformatics and Computational Biology, A. C. Camargo Cancer Center, São Paulo, SP 01509-010, Brazil. 3. Laboratory of Medical Genomics, A. C. Camargo Cancer Center, São Paulo, SP 01509-010, Brazil. 4. Laboratory of Neurosciences (LIM27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, SP 05403-903, Brazil. 5. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Abstract
MOTIVATION: Mutational signatures can be used to understand cancer origins and provide a unique opportunity to group tumor types that share the same origins and result from similar processes. These signatures have been identified from high throughput sequencing data generated from cancer genomes by using non-negative matrix factorisation (NMF) techniques. Current methods based on optimization techniques are strongly sensitive to initial conditions due to high dimensionality and nonconvexity of the NMF paradigm. In this context, an important question consists in the determination of the actual number of signatures that best represent the data. The extraction of mutational signatures from high-throughput data still remains a daunting task. RESULTS: Here we present a new method for the statistical estimation of mutational signatures based on an empirical Bayesian treatment of the NMF model. While requiring minimal intervention from the user, our method addresses the determination of the number of signatures directly as a model selection problem. In addition, we introduce two new concepts of significant clinical relevance for evaluating the mutational profile. The advantages brought by our approach are shown by the analysis of real and synthetic data. The later is used to compare our approach against two alternative methods mostly used in the literature and with the same NMF parametrization as the one considered here. Our approach is robust to initial conditions and more accurate than competing alternatives. It also estimates the correct number of signatures even when other methods fail. Results on real data agree well with current knowledge. AVAILABILITY AND IMPLEMENTATION: signeR is implemented in R and C ++, and is available as a R package at http://bioconductor.org/packages/signeR CONTACT: itojal@cipe.accamargo.org.brSupplementary information: Supplementary data are available at Bioinformatics online.
MOTIVATION: Mutational signatures can be used to understand cancer origins and provide a unique opportunity to group tumor types that share the same origins and result from similar processes. These signatures have been identified from high throughput sequencing data generated from cancer genomes by using non-negative matrix factorisation (NMF) techniques. Current methods based on optimization techniques are strongly sensitive to initial conditions due to high dimensionality and nonconvexity of the NMF paradigm. In this context, an important question consists in the determination of the actual number of signatures that best represent the data. The extraction of mutational signatures from high-throughput data still remains a daunting task. RESULTS: Here we present a new method for the statistical estimation of mutational signatures based on an empirical Bayesian treatment of the NMF model. While requiring minimal intervention from the user, our method addresses the determination of the number of signatures directly as a model selection problem. In addition, we introduce two new concepts of significant clinical relevance for evaluating the mutational profile. The advantages brought by our approach are shown by the analysis of real and synthetic data. The later is used to compare our approach against two alternative methods mostly used in the literature and with the same NMF parametrization as the one considered here. Our approach is robust to initial conditions and more accurate than competing alternatives. It also estimates the correct number of signatures even when other methods fail. Results on real data agree well with current knowledge. AVAILABILITY AND IMPLEMENTATION: signeR is implemented in R and C ++, and is available as a R package at http://bioconductor.org/packages/signeR CONTACT: itojal@cipe.accamargo.org.brSupplementary information: Supplementary data are available at Bioinformatics online.
Authors: Nitya Raj; Ronak Shah; Zsofia Stadler; Semanti Mukherjee; Joanne Chou; Brian Untch; Janet Li; Virginia Kelly; Leonard B Saltz; Diana Mandelker; Marc Ladanyi; Michael F Berger; David S Klimstra; Diane Reidy-Lagunes; Muyinat Osoba Journal: JCO Precis Oncol Date: 2018-04-19