Quantification of multicellular colonization in tumor metastasis using exome-sequencing data

Jo Nishino, Shuichi Watanabe, Fuyuki Miya, Takashi Kamatani, Toshitaka Sugawara, Keith A. Boroevich, Tatsuhiko Tsunoda

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Metastasis is a major cause of cancer-related mortality, and it is essential to understand how metastasis occurs in order to overcome it. One relevant question is the origin of a metastatic tumor cell population. Although the hypothesis of a single-cell origin for metastasis from a primary tumor has long been prevalent, several recent studies using mouse models have supported a multicellular origin of metastasis. Human bulk whole-exome sequencing (WES) studies also have demonstrated a multiple “clonal” origin of metastasis, with different mutational compositions. Specifically, there has not yet been strong research to determine how many founder cells colonize a metastatic tumor. To address this question, under the metastatic model of “single bottleneck followed by rapid growth,” we developed a method to quantify the “founder cell population size” in a metastasis using paired WES data from primary and metachronous metastatic tumors. Simulation studies demonstrated the proposed method gives unbiased results with sufficient accuracy in the range of realistic settings. Applying the proposed method to real WES data from four colorectal cancer patients, all samples supported a multicellular origin of metastasis and the founder size was quantified, ranging from 3 to 17 cells. Such a wide-range of founder sizes estimated by the proposed method suggests that there are large variations in genetic similarity between primary and metastatic tumors in the same subjects, which may explain the observed (dis)similarity of drug responses between tumors.

Original languageEnglish
Pages (from-to)2488-2497
Number of pages10
JournalInternational Journal of Cancer
Volume146
Issue number9
DOIs
Publication statusPublished - 2020 May 1
Externally publishedYes

Keywords

  • exome sequencing
  • founder population size
  • metastasis
  • multicellular colonization

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Quantification of multicellular colonization in tumor metastasis using exome-sequencing data'. Together they form a unique fingerprint.

Cite this