. 2023 Feb 8;115(2):165-173.

doi: 10.1093/jnci/djac215.

Body mass index and molecular subtypes of colorectal cancer

Neil Murphy¹, Christina C Newton², Mingyang Song^{3

4

5

6}, Nikos Papadimitriou¹, Michael Hoffmeister⁷, Amanda I Phipps⁸, Tabitha A Harrison⁸, Polly A Newcomb⁸, Elom K Aglago⁹, Sonja I Berndt¹⁰, Hermann Brenner⁷, Daniel D Buchanan^{11

12

13}, Yin Cao^{14

15

16}, Andrew T Chan^{5

6

17}, Xuechen Chen^{7

18}, Iona Cheng¹⁹, Jenny Chang-Claude^{20

21}, Niki Dimou¹, David Drew^{5

6}, Alton B Farris²², Amy J French²³, Steven Gallinger²⁴, Peter Georgeson^{11

12}, Marios Giannakis^{25

26}, Graham G Giles^{27

28

29}, Stephen B Gruber³⁰, Sophia Harlid³¹, Li Hsu^{8

32}, Wen-Yi Huang¹⁰, Mark A Jenkins²⁸, Ruhina S Laskar¹, Loic Le Marchand³³, Paul Limburg³⁴, Yi Lin⁸, Marko Mandic⁷, Johnathan A Nowak³⁵, Mereia Obón-Santacana^{36

37

38}, Shuji Ogino^{3

25

35

39}, Conghui Qu⁸, Lori C Sakoda^{8

40}, Robert E Schoen⁴¹, Melissa C Southey^{42

27

29}, Zsofia K Stadler⁴³, Robert S Steinfelder⁸, Wei Sun⁸, Stephen N Thibodeau³⁴, Amanda E Toland⁴⁴, Quang M Trinh⁴⁵, Kostas K Tsilidis^{9

46}, Tomotaka Ugai^{3

35}, Bethany Van Guelpen^{31

47}, Xiaoliang Wang⁸, Michael O Woods⁴⁸, Syed H Zaidi⁴⁵, Marc J Gunter¹, Ulrike Peters^{8

49}, Peter T Campbell⁵⁰

Affiliations

¹ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
² Population Science Department, American Cancer Society (ACS), Atlanta, GA, USA.
³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁴ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁹ Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
¹⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹¹ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia.
¹² University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia.
¹³ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia.
¹⁴ Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA.
¹⁵ Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
¹⁶ Alvin J. Siteman Cancer Center, St Louis, MO, USA.
¹⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁸ Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
¹⁹ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
²⁰ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²¹ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
²² Department of Pathology, Emory University, Atlanta, GA, USA.
²³ Division of Laboratory Genetics, Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
²⁴ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
²⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
²⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁷ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
²⁸ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
²⁹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
³⁰ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
³¹ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
³² Department of Biostatistics, University of Washington, Seattle, WA, USA.
³³ University of Hawaii Cancer Center, Epidemiology Program, Honolulu, HI, USA.
³⁴ Mayo Clinic, Rochester, MN, USA.
³⁵ Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³⁶ Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain.
³⁷ ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
³⁸ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
³⁹ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴⁰ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁴¹ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁴² Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
⁴³ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴⁴ Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁴⁵ Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁴⁶ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
⁴⁷ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
⁴⁸ Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL, Canada.
⁴⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁰ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

PMID: 36445035
PMCID: PMC9905970
DOI: 10.1093/jnci/djac215

Body mass index and molecular subtypes of colorectal cancer

Neil Murphy et al. J Natl Cancer Inst. 2023.

. 2023 Feb 8;115(2):165-173.

doi: 10.1093/jnci/djac215.

Authors

Affiliations

¹ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
² Population Science Department, American Cancer Society (ACS), Atlanta, GA, USA.
³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁴ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁹ Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
¹⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹¹ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia.
¹² University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia.
¹³ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia.
¹⁴ Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA.
¹⁵ Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
¹⁶ Alvin J. Siteman Cancer Center, St Louis, MO, USA.
¹⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁸ Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
¹⁹ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
²⁰ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²¹ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
²² Department of Pathology, Emory University, Atlanta, GA, USA.
²³ Division of Laboratory Genetics, Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
²⁴ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
²⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
²⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁷ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
²⁸ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
²⁹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
³⁰ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
³¹ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
³² Department of Biostatistics, University of Washington, Seattle, WA, USA.
³³ University of Hawaii Cancer Center, Epidemiology Program, Honolulu, HI, USA.
³⁴ Mayo Clinic, Rochester, MN, USA.
³⁵ Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³⁶ Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain.
³⁷ ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
³⁸ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
³⁹ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴⁰ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁴¹ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁴² Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
⁴³ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴⁴ Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁴⁵ Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁴⁶ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
⁴⁷ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
⁴⁸ Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL, Canada.
⁴⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁰ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

PMID: 36445035
PMCID: PMC9905970
DOI: 10.1093/jnci/djac215

Abstract

Background: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease.

Methods: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables.

Results: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control).

Conclusions: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.

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Figures

**Figure 1.**
Association between body mass index and Jass classified types of colorectal cancer. Controls were used as reference for all odds ratios. Odds ratios were adjusted for study, age, sex, smoking status, education, and red meat intake. Multinomial logistic regression was used to compare each type with the reference group (Type 4; P_difference). CI = confidence interval; CIMP = CpG island methylator phenotype; MSI = microsatellite instability; MSS = microsatellite stable; mut = mutated; OR = odds ratio; wild = wild type.

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Comment in

Combined individual participant data: highest-level evidence on obesity and colorectal cancer molecular subtypes.
Colditz GA. Colditz GA. J Natl Cancer Inst. 2023 Feb 8;115(2):120-121. doi: 10.1093/jnci/djac216. J Natl Cancer Inst. 2023. PMID: 36445026 Free PMC article. No abstract available.

References

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Body mass index and molecular subtypes of colorectal cancer

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Body mass index and molecular subtypes of colorectal cancer

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