Identifying Patient-specific Flow of Signal Transduction Perturbed by Multiple Single-nucleotide Alterations

Background: Identifying patient-specific flow of signal transduction perturbed by multiple single-nucleotide alterations is critical for improving patient outcomes in cancer cases. However, accurate estimation of mutational effects at the pathway level for such patients remains an open problem. While probabilistic pathway topology methods are gaining interest among the scientific community, the overwhelming majority do not account for network perturbation effects from multiple single-nucleotide alterations.  

Methods: Here we present an improvement of the Mutational Forks formalism to infer the patient-specific flow of signal transduction based on multiple single-nucleotide alterations, including non-synonymous and synonymous mutations. The lung adenocarcinoma and skin cutaneous melanoma datasets from TCGA Pan-Cancer Atlas have been employed to show the utility of the proposed method.  

Results: We have comprehensively characterized six mutational forks. The number of mutated nodes ranged from one to four depending on the topological characteristics of a fork. Transitional confidences (TCs) have been computed for every possible combination of single-nucleotide alterations in the fork. The performed analysis demonstrated the capacity of the Mutational Forks formalism to follow a biologically explainable logic in the identification of high likelihood signaling routes in lung adenocarcinoma and skin cutaneous melanoma patients. The findings have been largely supported by the evidence from the biomedical literature.  

Conclusions: We conclude that the formalism has a great chance to enable an assessment of patient-specific flow by leveraging information from multiple single-nucleotide alterations to adjust the transitional likelihoods that are solely based on the canonical view of a disease.  

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