A Probabilistic Approach to Estimate the Temporal Order of Pathway Mutations Accounting for Intra-Tumor Heterogeneity

Menghan Wang, Yanqi Xie, Jinpeng Liu, Austin Li, Li Chen, Arnold Stromberg, Susanne M. Arnold, Chunming Liu, Chi Wang

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The development of cancer involves the accumulation of somatic mutations in several essential biological pathways. Delineating the temporal order of pathway mutations during tumorigenesis is crucial for comprehending the biological mechanisms underlying cancer development and identifying potential targets for therapeutic intervention. Several computational and statistical methods have been introduced for estimating the order of somatic mutations based on mutation profile data from a cohort of patients. However, one major issue of current methods is that they do not take into account intra-tumor heterogeneity (ITH), which limits their ability to accurately discern the order of pathway mutations. To address this problem, we propose PATOPAI, a probabilistic approach to estimate the temporal order of mutations at the pathway level by incorporating ITH information as well as pathway and functional annotation information of mutations. PATOPAI uses a maximum likelihood approach to estimate the probability of pathway mutational events occurring in a specific sequence, wherein it focuses on the orders that are consistent with the phylogenetic structure of the tumors. Applications to whole exome sequencing data from The Cancer Genome Atlas (TCGA) illustrate our method’s ability to recover the temporal order of pathway mutations in several cancer types.

Original languageEnglish
Article number2488
JournalCancers
Volume16
Issue number13
DOIs
StatePublished - Jul 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

Funding

This research was supported by the National Institutes of Health [R03CA259670, UL1TR001998], and the Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky\u2019s Markey Cancer Center [P30CA177558].

FundersFunder number
The Markey Biostatistics and Bioinformatics Shared Resource Facility
National Institutes of Health (NIH)UL1TR001998, R03CA259670
National Institutes of Health (NIH)
University of Kentucky Markey Cancer CenterP30CA177558
University of Kentucky Markey Cancer Center

    Keywords

    • cancer mutations
    • intra-tumor heterogeneity
    • pathway analysis

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Fingerprint

    Dive into the research topics of 'A Probabilistic Approach to Estimate the Temporal Order of Pathway Mutations Accounting for Intra-Tumor Heterogeneity'. Together they form a unique fingerprint.

    Cite this