Impaired tumor immune response in metastatic tumors is a selective pressure for neutral evolution in CRC cases

Shotaro Sakimura, Satoshi Nagayama, Mitsuko Fukunaga, Qingjiang Hu, Akihiro Kitagawa, Yuta Kobayashi, Takanori Hasegawa, Miwa Noda, Yuta Kouyama, Dai Shimizu, Tomoko Saito, Atsushi Niida, Yusuke Tsuruda, hajime otsu, Yoshihiro Matsumoto, Hiroki Uchida, Takaaki Masuda, Keishi Sugimachi, Shin Sasaki, Kazutaka YamadaKazuki Takahashi, Hideki Innan, Yutaka Suzuki, Hiromi Nakamura, Yasushi Totoki, Shinichi Mizuno, Masanobu Ohshima, Tatsuhiro Shibata, Koshi Mimori

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

A Darwinian evolutionary shift occurs early in the neutral evolution of advanced colorectal carcinoma (CRC), and copy number aberrations (CNA) are essential in the transition from adenoma to carcinoma. In light of this primary evolution, we investigated the evolutionary principles of the genome that foster postoperative recurrence of CRC. CNA and neoantigens (NAG) were compared between early primary tumors with recurrence (CRCR) and early primary tumors without recurrence (precancerous and early; PCRC). We compared CNA, single nucleotide variance (SNV), RNA sequences, and T-cell receptor (TCR) repertoire between 9 primary and 10 metastatic sites from 10 CRCR cases. We found that NAG in primary sites were fewer in CRCR than in PCRC, while the arm level CNA were significantly higher in primary sites in CRCR than in PCRC. Further, a comparison of genomic aberrations of primary and metastatic conditions revealed no significant differences in CNA. The driver mutations in recurrence were the trunk of the evolutionary phylogenic tree from primary sites to recurrence sites. Notably, PD-1 and TIM3, T cell exhaustion-related molecules of the tumor immune response, were abundantly expressed in metastatic sites compared to primary sites along with the increased number of CD8 expressing cells. The postoperative recurrence-free survival period was only significantly associated with the NAG levels and TCR repertoire diversity in metastatic sites. Therefore, CNA with diminished NAG and diverse TCR repertoire in pre-metastatic sites may determine postoperative recurrence of CRC.

Original languageEnglish
Article numbere1009113
JournalPLoS genetics
Volume17
Issue number1
DOIs
Publication statusPublished - Jan 21 2021

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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