Feb 24, 2016

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

American Journal of Human Genetics
Xing HuaJianxin Shi

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 associa...Continue Reading

  • References38
  • Citations6

References

Mentioned in this Paper

TP53 gene
Genome-Wide Association Study
Study
EGFR
Biochemical Pathway
RUNX1 gene
FLT3
Lymphoma, Non-Hodgkin
NRAS gene
N-ras Genes

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