1: Landscape and function of multiple mutations within individual oncogenes.
Science of the Month - June 2020
Nature,
8 April 2020, DOI:10.1038/s41586-020-2175-2
Yuki Saito, Junji Koya, Mitsugu Araki, Yasunori Kogure, Sumito Shingaki, Mariko Tabata, Marni B. McClure, Kota Yoshifuji, Shigeyuki Matsumoto, Yuta Isaka, Hiroko Tanaka, Takanori Kanai, Satoru Miyano, Yuichi Shiraishi, Yasushi Okuno & Keisuke Kataoka
Although large-scale cancer genome analysis studies in recent years have identified various oncogene abnormalities, their full scope and functional significance are not yet fully understood. Therefore, we conducted a cross-cancer analysis using a supercomputer on large-scale cancer genome data from approximately 60,000 cases, the largest number of cases to date, and elucidated a new carcinogenic mechanism in which multiple mutations within the same oncogene function synergistically. While it was conventionally thought that oncogenes often have single mutations at specific sites (hotspots), we found that many cases actually had multiple mutations in various oncogenes, such as the PIK3CA gene. Through multi-omics analysis and functional analyses using cell lines and mice, we found that multiple mutations within the same oncogene exhibit a synergistic effect, showing a strong, coordinated oncogenic-promoting effect even if the mutations are functionally weak on their own. The findings of this study are a discovery that could provide fundamental knowledge for cancer genetics, and its application to cancer genomic medicine is anticipated.
(Yuki Saito, Class of '94, Department of Gastroenterology and Hepatology)
2: Somatic inflammatory gene mutations in human ulcerative colitis epithelium.
Nature.
Nanki K, Fujii M, Shimokawa M, Matano M, Nishikori S, Date S, Takano A, Toshimitsu K, Ohta Y, Takahashi S, Sugimoto S, Ishimaru K, Kawasaki K, Nagai Y, Ishii R, Yoshida K, Sasaki N, Hibi T, Ishihara S, Kanai T, Sato T.
—survival of the fittest— The principle that individuals adapted to their environment are selected, is the driving force of biological evolution. We have now demonstrated for the first time that adaptive evolution also exists within the human body. The colonic epithelium constantly accumulates gene mutations, and if a mutation unfortunately occurs in an oncogene, it becomes a "cancer" that proliferates regardless of the environment. In this study, we discovered the existence of "adaptive mutations," which are different from carcinogenic mutations. The mucosa in ulcerative colitis is rich in IL-17, an inflammatory cytokine that induces cell death in the epithelium. For this reason, mutated epithelial cells that cannot activate IL-17 signaling escape the attack of IL-17 and exhibit selective clonal expansion. These mutant clones expand while adapting to their environment, changing the body's immune response without exhibiting cancer-like morphological changes. Until now, somatic mutations have been treated as an enemy, equated with cancer mutations. This new type of mutation, the "adaptive mutation"—is it our ally or our enemy? Future research will be interesting.
(Toshiro Sato, Class of '76, Department of Organoid Medical Sciences; Masayuki Fujii, equivalent to Class of '85; Kosaku Nanki, Class of '86, Department of Gastroenterology)
Other Published Papers
1: CYP2D6 Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study
Journal of Clinical Oncology.
Tamura K, Imamura CK, Takano T, Saji S, Yamanaka T, Yonemori K, Takahashi M, Tsurutani J, Nishimura R, Sato K, Kitani A, Ueno NT, Mushiroda T, Kubo M, Fujiwara Y, Tanigawara Y.
2: Chromosome Engineering of Human Colon-Derived Organoids to Develop a Model of Traditional Serrated Adenoma.
Gastroenterology.
Kawasaki K, Fujii M, Sugimoto S, Ishikawa K, Matano M, Ohta Y, Toshimitsu K, Takahashi S, Hosoe N, Sekine S, Kanai T, Sato T.
3: Dual Programmed Death Receptor-1 and Vascular Endothelial Growth Factor Receptor-2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma.
Hepatology.
Shigeta K, Datta M, Hato T, Kitahara S, Chen IX, Matsui A, Kikuchi H, Mamessier E, Aoki S, Ramjiawan RR, Ochiai H, Bardeesy N, Huang PG, Cobbold M, Zhu ARX, Jain RK, Duda DG.