Keisuke Kosumi1, Tsuyoshi Hamada2, Sui Zhang3, Li Liu4, Annacarolina da Silva2, Hideo Koh5, Tyler S Twombly2, Kosuke Mima1, Teppei Morikawa6, Mingyang Song7, Jonathan A Nowak8, Reiko Nishihara9, Leonard B Saltz10, Donna Niedzwiecki11, Fang-Shu Ou12, Tyler Zemla12, Robert J Mayer3, Hideo Baba13, Kimmie Ng3, Marios Giannakis14, Xuehong Zhang15, Kana Wu16, Edward L Giovannucci16, Andrew T Chan17, Charles S Fuchs18, Jeffrey A Meyerhardt3, Shuji Ogino19. 1. Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan. 2. Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. 3. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. 4. Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, PR China. 5. Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan. 6. Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 7. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. 8. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 9. Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 10. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 11. Alliance Statistics and Data Center and Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA. 12. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA. 13. Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan. 14. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 15. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 16. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 17. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 18. Yale Cancer Center, New Haven, CT, USA; Department of Medicine, Yale School of Medicine, New Haven, CT, USA; Smilow Cancer Hospital, New Haven, CT, USA. 19. Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: shuji_ogino@dfci.harvard.edu.
Abstract
BACKGROUND: Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2, COX-2)-prostaglandin E2 (PGE2) pathway promotes tumour progression. Considering evidence suggesting increased PGE2 synthesis by BRAF mutation in tumour cells, we hypothesised that the association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality might be stronger in BRAF-mutated tumours than in BRAF-wild-type tumours. METHODS: Using 1708 patients, including 1200 stage I-IV colorectal carcinoma cases in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) and 508 stage III colon cancer cases in a National Cancer Institute-sponsored randomised controlled trial of adjuvant therapy (CALGB/Alliance 89803), we evaluated tumour PTGS2 (COX-2) expression status using immunohistochemistry. We examined the prognostic association of PTGS2 (COX-2) expression in strata of BRAF mutation status by multivariable Cox proportional hazards regression models to adjust for potential confounders, including disease stage, tumour differentiation, microsatellite instability status and KRAS and PIK3CA mutations. RESULTS: In NHS and HPFS, the association of PTGS2 (COX-2) expression with colorectal cancer-specific survival differed by BRAF mutation status (Pinteraction = 0.0005); compared with PTGS2 (COX-2)-negative/low carcinomas, the multivariable-adjusted hazard ratios for PTGS2 (COX-2)-high carcinomas were 2.44 (95% confidence interval, 1.39-4.28) in BRAF-mutated cases and 0.82 (95% confidence interval, 0.65-1.04) in BRAF-wild-type cases. Differential prognostic associations of PTGS2 (COX-2) expression in strata of BRAF mutation status were similarly observed in CALGB/Alliance 89803 trial (Pinteraction = 0.03). CONCLUSIONS: The association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality is stronger in BRAF-mutated tumours than in BRAF-wild-type tumours, supporting interactive roles of PTGS2 (COX-2) expression and BRAF mutation statuses in prognostication of patients with colorectal cancer; ClinicalTrials.gov Identifier, NCT00003835.
BACKGROUND:Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2, COX-2)-prostaglandin E2 (PGE2) pathway promotes tumour progression. Considering evidence suggesting increased PGE2 synthesis by BRAF mutation in tumour cells, we hypothesised that the association of tumourPTGS2 (COX-2) expression with colorectal cancermortality might be stronger in BRAF-mutated tumours than in BRAF-wild-type tumours. METHODS: Using 1708 patients, including 1200 stage I-IV colorectal carcinoma cases in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) and 508 stage III colon cancer cases in a National Cancer Institute-sponsored randomised controlled trial of adjuvant therapy (CALGB/Alliance 89803), we evaluated tumourPTGS2 (COX-2) expression status using immunohistochemistry. We examined the prognostic association of PTGS2 (COX-2) expression in strata of BRAF mutation status by multivariable Cox proportional hazards regression models to adjust for potential confounders, including disease stage, tumour differentiation, microsatellite instability status and KRAS and PIK3CA mutations. RESULTS: In NHS and HPFS, the association of PTGS2 (COX-2) expression with colorectal cancer-specific survival differed by BRAF mutation status (Pinteraction = 0.0005); compared with PTGS2 (COX-2)-negative/low carcinomas, the multivariable-adjusted hazard ratios for PTGS2 (COX-2)-high carcinomas were 2.44 (95% confidence interval, 1.39-4.28) in BRAF-mutated cases and 0.82 (95% confidence interval, 0.65-1.04) in BRAF-wild-type cases. Differential prognostic associations of PTGS2 (COX-2) expression in strata of BRAF mutation status were similarly observed in CALGB/Alliance 89803 trial (Pinteraction = 0.03). CONCLUSIONS: The association of tumourPTGS2 (COX-2) expression with colorectal cancermortality is stronger in BRAF-mutated tumours than in BRAF-wild-type tumours, supporting interactive roles of PTGS2 (COX-2) expression and BRAF mutation statuses in prognostication of patients with colorectal cancer; ClinicalTrials.gov Identifier, NCT00003835.
Authors: Shuji Ogino; Kaori Shima; Jeffrey A Meyerhardt; Nadine J McCleary; Kimmie Ng; Donna Hollis; Leonard B Saltz; Robert J Mayer; Paul Schaefer; Renaud Whittom; Alexander Hantel; Al B Benson; Donna Spiegelman; Richard M Goldberg; Monica M Bertagnolli; Charles S Fuchs Journal: Clin Cancer Res Date: 2011-12-06 Impact factor: 12.531
Authors: Shuji Ogino; Katsuhiko Nosho; Gregory J Kirkner; Takako Kawasaki; Jeffrey A Meyerhardt; Massimo Loda; Edward L Giovannucci; Charles S Fuchs Journal: Gut Date: 2008-10-02 Impact factor: 23.059
Authors: Mai Yamauchi; Teppei Morikawa; Aya Kuchiba; Yu Imamura; Zhi Rong Qian; Reiko Nishihara; Xiaoyun Liao; Levi Waldron; Yujin Hoshida; Curtis Huttenhower; Andrew T Chan; Edward Giovannucci; Charles Fuchs; Shuji Ogino Journal: Gut Date: 2012-03-17 Impact factor: 23.059
Authors: Xiaoyun Liao; Paul Lochhead; Reiko Nishihara; Teppei Morikawa; Aya Kuchiba; Mai Yamauchi; Yu Imamura; Zhi Rong Qian; Yoshifumi Baba; Kaori Shima; Ruifang Sun; Katsuhiko Nosho; Jeffrey A Meyerhardt; Edward Giovannucci; Charles S Fuchs; Andrew T Chan; Shuji Ogino Journal: N Engl J Med Date: 2012-10-25 Impact factor: 91.245
Authors: T M Becker; S C Boyd; B Mijatov; K Gowrishankar; S Snoyman; G M Pupo; R A Scolyer; G J Mann; R F Kefford; X D Zhang; H Rizos Journal: Oncogene Date: 2013-03-04 Impact factor: 9.867
Authors: C Göbel; F Breitenbuecher; H Kalkavan; P S Hähnel; S Kasper; S Hoffarth; K Merches; H Schild; K S Lang; M Schuler Journal: Cell Death Dis Date: 2014-12-11 Impact factor: 8.469
Authors: Reiko Nishihara; Paul Lochhead; Aya Kuchiba; Seungyoun Jung; Mai Yamauchi; Xiaoyun Liao; Yu Imamura; Zhi Rong Qian; Teppei Morikawa; Molin Wang; Donna Spiegelman; Eunyoung Cho; Edward Giovannucci; Charles S Fuchs; Andrew T Chan; Shuji Ogino Journal: JAMA Date: 2013-06-26 Impact factor: 56.272