Adaptation of a Mutual Exclusivity Framework to Identify Driver Mutations within Biological Pathways

Distinguishing genomic alterations in cancer genes that have functional impact on tumor growth and disease progression from the ones that are passengers and confer no fitness advantage has important clinical implications. Evidence-based methods for nominating drivers are limited by existing knowledge on the oncogenic effects and therapeutic benefits of specific variants from clinical trials or experimental settings. As clinical sequencing becomes a mainstay of patient care, applying computational methods to mine the rapidly growing clinical genomic data holds promise in uncovering novel functional candidates beyond the existing knowledge-base and expanding the patient population that could potentially benefit from genetically targeted therapies. We propose a statistical and computational method (MAGPIE) that builds on a likelihood approach leveraging the mutual exclusivity pattern within an oncogenic pathway for identifying probabilistically both the specific genes within a pathway and the individual mutations within such genes that are truly the drivers. Alterations in a cancer gene are assumed to be a mixture of driver and passenger mutations with the passenger rates modeled in relationship to tumor mutational burden. A limited memory BFGS algorithm is used to facilitate large scale optimization. We use simulations to study the operating characteristics of the method and assess false positive and false negative rates in driver nomination. When applied to a large study of primary melanomas the method accurately identified the known driver genes within the RTK-RAS pathway and nominated a number of rare variants with previously unknown biological and clinical relevance as prime candidates for functional validation.