Takeshi Kajiwara1, Tomohiro Nishina2, Akio Nakasya2, Natsumi Yamashita3, Riu Yamashita4, Yoshiaki Nakamura5, Manabu Shiozawa6, Satoshi Yuki7, Hiroya Taniguchi8, Hiroki Hara9, Takashi Ohta10, Taito Esaki11, Eiji Shinozaki12, Atsuo Takashima13, Toshikazu Moriwaki14, Tadamichi Denda15, Koushiro Ohtsubo16, Yu Sunakawa17, Yosuke Horita18, Hisato Kawakami19, Takeshi Kato20, Taroh Satoh21, Koji Ando22, Tomonori Mizutani23, Hisateru Yasui24, Masahiro Goto25, Hiroyuki Okuyama26, Kentaro Yamazaki27, Takayuki Yoshino5, Ichinosuke Hyodo2. 1. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan. kajiwara.takeshi.wv@mail.hosp.go.jp. 2. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama, Ehime, 791-0280, Japan. 3. Clinical Research Center, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan. 4. Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan. 5. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 6. Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan. 7. Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan. 8. Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. 9. Department of Gastroenterology, Saitama Cancer Center, Kitaadachi-gun, Japan. 10. Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Japan. 11. Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. 12. Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. 13. Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. 14. Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 15. Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan. 16. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 17. Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan. 18. Department of Medical Oncology, Saitama Medical University International Medical Center, Hidaka, Japan. 19. Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Japan. 20. Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan. 21. Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Japan. 22. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 23. Department of General Medicine, Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan. 24. Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan. 25. Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan. 26. Department of Clinical Oncology, Kagawa University Hospital, Kita-gun, Japan. 27. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shunto-gun, Japan.
Abstract
PURPOSE: Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. METHODS: Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. RESULTS: The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. CONCLUSION: NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker.
PURPOSE: Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. METHODS: Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. RESULTS: The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. CONCLUSION: NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker.
Authors: John J Arcaroli; W M Tai; Ryan McWilliams; Stacey Bagby; Patrick J Blatchford; Marileila Varella-Garcia; Alicia Purkey; Kevin S Quackenbush; Eun-Kee Song; Todd M Pitts; Dexiang Gao; Chris Lieu; Martine McManus; Aik Choon Tan; Xianxian Zheng; Qin Zhang; Mark Ozeck; Peter Olson; Zhi-Qin Jiang; Scott Kopetz; Antonio Jimeno; Stephen Keysar; Gail Eckhardt; Wells A Messersmith Journal: Int J Cancer Date: 2015-07-22 Impact factor: 7.396
Authors: R Ferrarotto; G Eckhardt; A Patnaik; P LoRusso; L Faoro; J V Heymach; A M Kapoun; L Xu; P Munster Journal: Ann Oncol Date: 2018-07-01 Impact factor: 32.976
Authors: Renata Ferrarotto; Yoshitsugu Mitani; Lixia Diao; Irene Guijarro; Jing Wang; Patrick Zweidler-McKay; Diana Bell; William N William; Bonnie S Glisson; Michael J Wick; Ann M Kapoun; Amita Patnaik; Gail Eckhardt; Pamela Munster; Leonardo Faoro; Jakob Dupont; J Jack Lee; Andrew Futreal; Adel K El-Naggar; John V Heymach Journal: J Clin Oncol Date: 2016-11-21 Impact factor: 44.544
Authors: Rene Jackstadt; Sander R van Hooff; Joshua D Leach; Xabier Cortes-Lavaud; Jeroen O Lohuis; Rachel A Ridgway; Valérie M Wouters; Jatin Roper; Timothy J Kendall; Campbell S Roxburgh; Paul G Horgan; Colin Nixon; Craig Nourse; Matthias Gunzer; William Clark; Ann Hedley; Omer H Yilmaz; Mamunur Rashid; Peter Bailey; Andrew V Biankin; Andrew D Campbell; David J Adams; Simon T Barry; Colin W Steele; Jan Paul Medema; Owen J Sansom Journal: Cancer Cell Date: 2019-09-16 Impact factor: 38.585