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

Autoři: Shotaro Sakimura aff001;  Satoshi Nagayama aff003;  Mitsuko Fukunaga aff001;  Qingjiang Hu aff001;  Akihiro Kitagawa aff001;  Yuta Kobayashi aff001;  Takanori Hasegawa aff004;  Miwa Noda aff001;  Yuta Kouyama aff001;  Dai Shimizu aff001;  Tomoko Saito aff001;  Atsushi Niida aff005;  Yusuke Tsuruda aff001;  Hajime Otsu aff001;  Yoshihiro Matsumoto aff001;  Hiroki Uchida aff001;  Takaaki Masuda aff001;  Keishi Sugimachi aff001;  Shin Sasaki aff006;  Kazutaka Yamada aff007;  Kazuki Takahashi aff008;  Hideki Innan aff008;  Yutaka Suzuki aff009;  Hiromi Nakamura aff010;  Yasushi Totoki aff010;  Shinichi Mizuno aff011;  Masanobu Ohshima aff012;  Tatsuhiro Shibata aff010;  Koshi Mimori aff001
Působiště autorů: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan aff001;  Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan aff002;  Gastroenterological Center, Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan aff003;  Division of Health Medical Data Science, Health Intelligence Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan aff004;  Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan aff005;  Department of Surgery, Omori Red Cross Hospital, Tokyo, Japan aff006;  Department of Surgery, Takano Hospital, Kumamoto, Japan aff007;  Department of Evolutionary Studies of Biosystems, SOKENDAI, The Graduate University for Advanced Studies, Tokyo, Japan aff008;  Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan aff009;  Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan aff010;  Center for Advanced Medical Innovation, Kyushu University, Fukuoka, Japan aff011;  Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan aff012;  Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan aff013
Vyšlo v časopise: Impaired tumor immune response in metastatic tumors is a selective pressure for neutral evolution in CRC cases. PLoS Genet 17(1): e1009113. doi:10.1371/journal.pgen.1009113
Kategorie: Research Article


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.

Klíčová slova:

Colorectal cancer – Metastasis – Cancer genomics – Evolutionary immunology – Immune response – Metastatic tumors – T cell receptors – T cells


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