NaNa Keum1,2, Li Liu3,4,5, Tsuyoshi Hamada4, Zhi Rong Qian4, Jonathan A Nowak6, Yin Cao7, Annacarolina da Silva4, Keisuke Kosumi4, Mingyang Song3,8,9, Daniel Nevo10,11, Molin Wang10,11, Andrew T Chan8,9,12, Jeffrey A Meyerhardt4, Charles S Fuchs13,14,15, Kana Wu3, Shuji Ogino3,4,6,11,16, Reiko Nishihara3,4,6,10,11, Xuehong Zhang12. 1. Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA. nak212@mail.harvard.edu. 2. Department of Food Science and Biotechnology, Dongguk University, Goyang, South Korea. nak212@mail.harvard.edu. 3. Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA. 4. Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. 5. 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, Hubei, People's Republic of China. 6. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 7. Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. 8. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 9. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. 10. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 11. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 12. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 13. Yale Cancer Center, New Haven, CT, USA. 14. Department of Medicine, Yale School of Medicine, New Haven, CT, USA. 15. Smilow Cancer Hospital, New Haven, CT, USA. 16. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Abstract
BACKGROUND: A preventive potential of high calcium intake against colorectal cancer has been indicated for distal colon cancer, which is inversely associated with high-level CpG island methylator phenotype (CIMP), high-level microsatellite instability (MSI), and BRAF and PIK3CA mutations. In addition, BRAF mutation is strongly inversely correlated with KRAS mutation. We hypothesized that the association between calcium intake and colon cancer risk might vary by these molecular features. METHODS: We prospectively followed 88,506 women from the Nurses' Health Study and 47,733 men from the Health Professionals Follow-up Study for up to 30 years. Duplication-method Cox proportional cause-specific hazards regression was used to estimate multivariable hazard ratios (HRs), and 95% confidence intervals (95% CIs) for the associations between calcium intake and the risk of colon cancer subtypes. By Bonferroni correction, the α-level was adjusted to 0.01. RESULTS: Based on 853 colon cancer cases, the inverse association between dietary calcium intake and colon cancer risk differed by CIMP status (pheterogeneity = 0.01). Per each 300 mg/day increase in intake, multivariable HRs were 0.84 (95% CI 0.76-0.94) for CIMP-negative/low and 1.12 (95% CI 0.93-1.34) for CIMP-high. Similar differential associations were suggested for MSI subtypes (pheterogeneity = 0.02), with the corresponding HR being 0.86 (95% CI 0.77-0.95) for non-MSI-high and 1.10 (95% CI 0.92-1.32) for MSI-high. No differential associations were observed by BRAF, KRAS, or PIK3CA mutations. CONCLUSION: The inverse association between dietary calcium intake and colon cancer risk may be specific to CIMP-negative/low and possibly non-MSI-high subtypes.
BACKGROUND: A preventive potential of high calcium intake against colorectal cancer has been indicated for distal colon cancer, which is inversely associated with high-level CpG island methylator phenotype (CIMP), high-level microsatellite instability (MSI), and BRAF and PIK3CA mutations. In addition, BRAF mutation is strongly inversely correlated with KRAS mutation. We hypothesized that the association between calcium intake and colon cancer risk might vary by these molecular features. METHODS: We prospectively followed 88,506 women from the Nurses' Health Study and 47,733 men from the Health Professionals Follow-up Study for up to 30 years. Duplication-method Cox proportional cause-specific hazards regression was used to estimate multivariable hazard ratios (HRs), and 95% confidence intervals (95% CIs) for the associations between calcium intake and the risk of colon cancer subtypes. By Bonferroni correction, the α-level was adjusted to 0.01. RESULTS: Based on 853 colon cancer cases, the inverse association between dietary calcium intake and colon cancer risk differed by CIMP status (pheterogeneity = 0.01). Per each 300 mg/day increase in intake, multivariable HRs were 0.84 (95% CI 0.76-0.94) for CIMP-negative/low and 1.12 (95% CI 0.93-1.34) for CIMP-high. Similar differential associations were suggested for MSI subtypes (pheterogeneity = 0.02), with the corresponding HR being 0.86 (95% CI 0.77-0.95) for non-MSI-high and 1.10 (95% CI 0.92-1.32) for MSI-high. No differential associations were observed by BRAF, KRAS, or PIK3CA mutations. CONCLUSION: The inverse association between dietary calcium intake and colon cancer risk may be specific to CIMP-negative/low and possibly non-MSI-high subtypes.
Authors: Kana Wu; Walter C Willett; Charles S Fuchs; Graham A Colditz; Edward L Giovannucci Journal: J Natl Cancer Inst Date: 2002-03-20 Impact factor: 13.506
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Authors: Eunyoung Cho; Stephanie A Smith-Warner; Donna Spiegelman; W Lawrence Beeson; Piet A van den Brandt; Graham A Colditz; Aaron R Folsom; Gary E Fraser; Jo L Freudenheim; Edward Giovannucci; R Alexandra Goldbohm; Saxon Graham; Anthony B Miller; Pirjo Pietinen; John D Potter; Thomas E Rohan; Paul Terry; Paolo Toniolo; Mikko J Virtanen; Walter C Willett; Alicja Wolk; Kana Wu; Shiaw-Shyuan Yaun; Anne Zeleniuch-Jacquotte; David J Hunter Journal: J Natl Cancer Inst Date: 2004-07-07 Impact factor: 13.506