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

Xing Hua, Paula L. Hyland, Jing Huang, Lei Song, Bin Zhu, Neil E. Caporaso, Maria Teresa Landi, Nilanjan Chatterjee, Jianxin Shi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)442-455
Number of pages14
JournalAmerican Journal of Human Genetics
Volume98
Issue number3
DOIs
Publication statusPublished - Mar 3 2016
Externally publishedYes

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Keywords

  • driver genes
  • mutual exclusivity
  • oncogenic pathways
  • tumor sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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