Inferring sequential order of somatic mutations during tumorgenesis based on markov chain model

Hao Kang, Kwang Hyun Cho, Xiaohua Douglas Zhang, Tao Zeng, Luonan Chen

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Tumors are developed and worsen with the accumulated mutations on DNA sequences during tumorigenesis. Identifying the temporal order of gene mutations in cancer initiation and development is a challenging topic. It not only provides a new insight into the study of tumorigenesis at the level of genome sequences but also is an effective tool for early diagnosis of tumors and preventive medicine. In this paper, we develop a novel method to accurately estimate the sequential order of gene mutations during tumorigenesis from genome sequencing data based on Markov chain model as TOMC (Temporal Order based on Markov Chain), and also provide a new criterion to further infer the order of samples or patients, which can characterize the severity or stage of the disease. We applied our method to the analysis of tumors based on several high-throughput datasets. Specifically, first, we revealed that tumor suppressor genes (TSG) tend to be mutated ahead of oncogenes, which are considered as important events for key functional loss and gain during tumorigenesis. Second, the comparisons of various methods demonstrated that our approach has clear advantages over the existing methods due to the consideration on the effect of mutation dependence among genes, such as co-mutation. Third and most important, our method is able to deduce the ordinal sequence of patients or samples to quantitatively characterize their severity of tumors. Therefore, our work provides a new way to quantitatively understand the development and progression of tumorigenesis based on high throughput sequencing data.

Original languageEnglish
Article number7110359
Pages (from-to)1094-1103
Number of pages10
JournalIEEE/ACM Transactions on Computational Biology and Bioinformatics
Volume12
Issue number5
DOIs
StatePublished - Sep 1 2015

Bibliographical note

Publisher Copyright:
© 2015 IEEE.

Keywords

  • first hitting time
  • markov chain
  • Mutation order

ASJC Scopus subject areas

  • Biotechnology
  • Genetics
  • Applied Mathematics

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