MEGSA: A Powerful and Flexible Framework for Analyzing Mutual Exclusivity of Tumor Mutations

• Published in: American journal of human genetics Vol. 98; no. 3; pp. 442 - 455
• Main Authors: Hua, Xing, Hyland, Paula L., Huang, Jing, Song, Lei, Zhu, Bin, Caporaso, Neil E., Landi, Maria Teresa, Chatterjee, Nilanjan, Shi, Jianxin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2016; Cell Press; Elsevier
• Subjects: Breast cancer; Breast Neoplasms - genetics; Cell Line, Tumor; Computational Biology - methods; Core Binding Factor Alpha 2 Subunit - genetics; driver genes; Female; fms-Like Tyrosine Kinase 3 - genetics; Genes; Genome-Wide Association Study; Genomes; GTP Phosphohydrolases - genetics; Humans; Isocitrate Dehydrogenase - genetics; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - genetics; Mediator Complex - genetics; Membrane Proteins - genetics; Models, Molecular; Mutation; mutual exclusivity; Nuclear Proteins - genetics; oncogenic pathways; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-kit - genetics; Receptors, Cytoplasmic and Nuclear - genetics; Repressor Proteins - genetics; Sequence Analysis, DNA; Simulation; Transcription Factors - genetics; tumor sequencing; Tumor Suppressor Protein p53 - genetics; oncogenic pathways; mutual exclusivity; tumor sequencing; driver genes
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2015.12.021

The central challenges in tumor sequencing studies is to identify driver genes and pathways, investigate their functional relationships, and nominate drug targets. The efficiency of these analyses, particularly for infrequently mutated genes, is compromised when subjects carry different combinations of driver mutations. Mutual exclusivity analysis helps address these challenges. To identify mutually exclusive gene sets (MEGS), we developed a powerful and flexible analytic framework based on a likelihood ratio test and a model selection procedure. Extensive simulations demonstrated that our method outperformed existing methods for both statistical power and the capability of identifying the exact MEGS, particularly for highly imbalanced MEGS. Our method can be used for de novo discovery, for pathway-guided searches, or for expanding established small MEGS. We applied our method to the whole-exome sequencing data for 13 cancer types from The Cancer Genome Atlas (TCGA). We identified multiple previously unreported non-pairwise MEGS in multiple cancer types. For acute myeloid leukemia, we identified a MEGS with five genes (FLT3, IDH2, NRAS, KIT, and TP53) and a MEGS (NPM1, TP53, and RUNX1) whose mutation status was strongly associated with survival (p = 6.7 × 10−4). For breast cancer, we identified a significant MEGS consisting of TP53 and four infrequently mutated genes (ARID1A, AKT1, MED23, and TBL1XR1), providing support for their role as cancer drivers.