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Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status

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Abstract

Previous studies suggest that abnormal energy balance status may dysregulate intestinal epithelial homeostasis and promote colorectal carcinogenesis, yet little is known about how host energy balance and obesity influence enterocyte differentiation during carcinogenesis. We hypothesized that the association between high body mass index (BMI) and colorectal carcinoma incidence might differ according to tumor histopathologic differentiation status. Using databases of the Nurses’ Health Study and Health Professionals Follow-up Study, and duplication-method Cox proportional hazards models, we prospectively examined an association between BMI and the incidence of colorectal carcinoma subtypes classified by differentiation features. 120,813 participants were followed for 26 or 32 years and 1528 rectal and colon cancer cases with available tumor pathological data were documented. The association between BMI and colorectal cancer risk significantly differed depending on the presence or absence of poorly-differentiated foci (Pheterogeneity = 0.006). Higher BMI was associated with a higher risk of colorectal carcinoma without poorly-differentiated foci (≥30.0 vs. 18.5–22.4 kg/m2: multivariable-adjusted hazard ratio, 1.87; 95% confidence interval, 1.49–2.34; Ptrend < 0.001), but not with risk of carcinoma with poorly-differentiated foci (Ptrend = 0.56). This differential association appeared to be consistent in strata of tumor microsatellite instability or FASN expression status, although the statistical power was limited. The association between BMI and colorectal carcinoma risk did not significantly differ by overall tumor differentiation, mucinous differentiation, or signet ring cell component (Pheterogeneity > 0.03, with the adjusted α of 0.01). High BMI was associated with risk of colorectal cancer subtype containing no poorly-differentiated focus. Our findings suggest that carcinogenic influence of excess energy balance might be stronger for tumors that retain better intestinal differentiation throughout the tumor areas.

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Abbreviations

AHEI:

Alternate Healthy Eating Index

BMI:

Body mass index

CI:

Confidence interval

FFPE:

Formalin-fixed paraffin-embedded

HPFS:

Health Professionals Follow-up Study

HR:

Hazard ratio

ISC:

Intestinal stem cells

METS:

Metabolic equivalent task score

MPE:

Molecular pathological epidemiology

MSI:

Microsatellite instability

MSS:

Microsatellite stable

NHS:

Nurses’ Health Study

NSAIDs:

Non-steroidal anti-inflammatory drugs

SD:

Standard deviation

WHO:

World Health Organization

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Acknowledgements

We would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

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Author notes

  1. Akiko Hanyuda, Yin Cao, Tsuyoshi Hamada, and Jonathan A. Nowak contributed equally as co-first authors. Charles S. Fuchs, Edward L. Giovannucci, Shuji Ogino, and Reiko Nishihara contributed equally as co-last authors.

Authors and Affiliations

  1. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Akiko Hanyuda, Yin Cao, Li Liu, Kana Wu, Mingyang Song, Edward L. Giovannucci & Reiko Nishihara

  2. Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan

    Akiko Hanyuda

  3. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Yin Cao, Mingyang Song & Andrew T. Chan

  4. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Yin Cao, Mingyang Song & Andrew T. Chan

  5. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Tsuyoshi Hamada, Zhi Rong Qian, Yohei Masugi, Annacarolina da Silva, Li Liu, Keisuke Kosumi, Jeffrey A. Meyerhardt, Charles S. Fuchs & Shuji Ogino

  6. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Jonathan A. Nowak, Thing Rinda Soong, Iny Jhun, Shuji Ogino & Reiko Nishihara

  7. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA

    Zhi Rong Qian, Kana Wu, Shuji Ogino & Reiko Nishihara

  8. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Xuehong Zhang, Andrew T. Chan, Charles S. Fuchs & Edward L. Giovannucci

  9. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Andrew T. Chan & Reiko Nishihara

  10. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Edward L. Giovannucci, Shuji Ogino & Reiko Nishihara

  11. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Reiko Nishihara

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  1. Akiko Hanyuda
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  2. Yin Cao
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  3. Tsuyoshi Hamada
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Corresponding authors

Correspondence to Shuji Ogino or Reiko Nishihara.

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This work was supported by US National Institutes of Health (NIH) Grants [UM1 CA186107 and P01 CA87969 to Meir J. Stampfer; P01 CA55075 and UM1 CA167552 to Walter C. Willett; K07 CA190673 to R.N.; R01 CA137178 and K24 DK098311 to A.T.C.; P50 CA127003 to C.S.F.; R01 CA151993 and R35 CA197735 to S.O.], by Nodal Award from the Dana-Farber Harvard Cancer Center (to S.O.); and by grants from the Project P Fund, the Friends of the Dana-Farber Cancer Institute, the Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. A.H. was supported by the Japan-United States Educational Exchange Promotion Foundation (Fulbright Foundation), Japan and the U.S. T.H. was supported by a fellowship grant from the Uehara Memorial Foundation and by a grant from the Mochida Memorial Foundation for Medical and Pharmaceutical Research. Y.M. was supported by a fellowship grant of the Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research. A.T.C. was a Damon Runyon Clinical Investigator.

Conflict of interest

A.T.C. previously served as a consultant for Bayer Healthcare, Pozen Inc, and Pfizer Inc. This study was not funded by Bayer Healthcare, Millennium Pharmaceuticals, or Pfizer Inc. All remaining authors have declared no conflicts of interest.

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We use HUGO (Human Genome Organisation)-approved official symbols for genes (italics) and gene products (non-italics), including CTNNB1, FASN, and PPARD; all of which are described at www.genenames.org.

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Hanyuda, A., Cao, Y., Hamada, T. et al. Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status. Eur J Epidemiol 32, 393–407 (2017). https://doi.org/10.1007/s10654-017-0254-y

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