title: Marine ω-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability.
abstract: BACKGROUND
  Chronic inflammation is involved in the development of colorectal cancer (CRC) and microsatellite instability (MSI), a distinct phenotype of CRC. Experimental evidence indicates an anti-inflammatory and antineoplastic effect of marine ω-3 polyunsaturated fatty acids (PUFAs). However, epidemiologic data remain inconclusive.
  
  
  METHODS
  We investigated whether the association between marine ω-3 PUFAs and CRC varies by MSI-defined subtypes of tumors in the Nurses' Health Study and Health Professionals Follow-up Study. We documented and classified 1125 CRC cases into either MSI-high tumors, in which 30% or more of the 10 microsatellite markers demonstrated instability, or microsatellite-stable (MSS) tumors. Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of MSS tumors and MSI-high tumors in relation to marine ω-3 PUFA intake. All statistical tests were two-sided.
  
  
  RESULTS
  Marine ω-3 PUFA intake was not associated with overall incidence of CRC. However, a statistically significant difference was detected by MSI status (P heterogeneity = .02): High marine ω-3 PUFA intake was associated with a lower risk of MSI-high tumors (comparing ≥0.30g/d with <0.10g/d: multivariable HR = 0.54, 95% CI = 0.35 to 0.83, P linearity = .03) but not MSS tumors (HR = 0.97, 95% CI = 0.78 to 1.20, P linearity = .28). This differential association appeared to be independent of CpG island methylator phenotype and BRAF mutation status.
  
  
  CONCLUSIONS
  High marine ω-3 PUFA intake is associated with lower risk of MSI-high CRC but not MSS tumors, suggesting a potential role of ω-3 PUFAs in protection against CRC through DNA mismatch repair. Further research is needed to confirm our findings and elucidate potential underlying mechanisms.
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Mingyang
authors: M
authors: Song
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Reiko
authors: R
authors: Nishihara
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Kana
authors: K
authors: Wu
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Zhi Rong
authors: ZR
authors: Qian
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Sun A
authors: SA
authors: Kim
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Yasutaka
authors: Y
authors: Sukawa
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Kosuke
authors: K
authors: Mima
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Kentaro
authors: K
authors: Inamura
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Atsuhiro
authors: A
authors: Masuda
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Juhong
authors: J
authors: Yang
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Charles S
authors: CS
authors: Fuchs
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Edward L
authors: EL
authors: Giovannucci
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Shuji
authors: S
authors: Ogino
authors: Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC).
authors: Andrew T
authors: AT
authors: Chan
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D015525:Fatty Acids, Omega-3 / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000150:complications / Q000517:prevention & control; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012306:Risk
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D015525:Fatty Acids, Omega-3; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf