Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature

Claire E Thomas^#¹, Peter Georgeson^#^{2

3}, Conghui Qu^#¹, Robert S Steinfelder¹, Daniel D Buchanan^{2

3

4}, Mingyang Song^{5

6

7}, Tabitha A Harrison¹, Caroline Y Um⁸, Meredith A Hullar¹, Mark A Jenkins⁹, Bethany Van Guelpen^{10

11}, Brigid M Lynch^{9

12}, Yohannes Adama Melaku^{12

13}, Jeroen R Huyghe¹, Elom K Aglago¹⁴, Sonja I Berndt¹⁵, Lisa A Boardman¹⁶, Peter T Campbell¹⁷, Yin Cao^{18

19

20}, Andrew T Chan^{7

21

22

23

24

25}, David A Drew²³, Jane C Figueiredo²⁶, Amy J French²⁷, Marios Giannakis^{28

29

30}, Ellen L Goode³¹, Stephen B Gruber³², Andrea Gsur³³, Marc J Gunter^{34

35}, Michael Hoffmeister³⁶, Li Hsu^{1

37}, Wen-Yi Huang¹⁵, Victor Moreno^{38

39

40

41}, Neil Murphy⁴², Polly A Newcomb^{1

43}, Christina C Newton⁸, Jonathan A Nowak^{44

45}, Mireia Obón-Santacana^{38

39

40}, Shuji Ogino^{44

46

47

29}, Wei Sun¹, Amanda E Toland⁴⁸, Quang M Trinh⁴⁹, Tomotaka Ugai⁷, Syed H Zaidi⁴⁹, Ulrike Peters^{1

43}, Amanda I Phipps^{1

43}

Affiliations

¹ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington.
² Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Australia.
³ University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, Australia.
⁴ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
⁶ Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
⁸ Department of Population Science, American Cancer Society, Atlanta, Georgia.
⁹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
¹⁰ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
¹¹ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
¹² Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
¹³ FHMRI Sleep, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
¹⁴ Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
¹⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
¹⁶ Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
¹⁷ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.
¹⁸ Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri.
¹⁹ Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.
²⁰ Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
²¹ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
²² Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
²³ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
²⁴ Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
²⁵ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
²⁶ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
²⁷ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
²⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
²⁹ Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
³⁰ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
³¹ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota.
³² Department of Medical Oncology and Therapeutics Research and Center for Precision Medicine, City of Hope National Medical Center, Duarte, California.
³³ Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
³⁴ Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
³⁵ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, UK.
³⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁷ Department of Biostatistics, University of Washington, Seattle, Washington.
³⁸ Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain.
³⁹ ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
⁴⁰ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁴¹ Department of Clinical Sciences, Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona, Spain.
⁴² Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
⁴³ Department of Epidemiology, University of Washington, Seattle, Washington.
⁴⁴ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
⁴⁵ Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
⁴⁶ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
⁴⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
⁴⁸ Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
⁴⁹ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

^# Contributed equally.

PMID: 38252034
PMCID: PMC10990777
DOI: 10.1158/1055-9965.EPI-23-0600

Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature

Claire E Thomas et al. Cancer Epidemiol Biomarkers Prev. 2024.

. 2024 Apr 3;33(4):534-546.

doi: 10.1158/1055-9965.EPI-23-0600.

Authors

Affiliations

¹ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington.
² Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Australia.
³ University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, Australia.
⁴ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
⁶ Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
⁸ Department of Population Science, American Cancer Society, Atlanta, Georgia.
⁹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
¹⁰ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
¹¹ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
¹² Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
¹³ FHMRI Sleep, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
¹⁴ Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
¹⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
¹⁶ Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
¹⁷ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.
¹⁸ Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri.
¹⁹ Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.
²⁰ Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
²¹ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
²² Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
²³ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
²⁴ Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
²⁵ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
²⁶ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
²⁷ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
²⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
²⁹ Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
³⁰ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
³¹ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota.
³² Department of Medical Oncology and Therapeutics Research and Center for Precision Medicine, City of Hope National Medical Center, Duarte, California.
³³ Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
³⁴ Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
³⁵ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, UK.
³⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁷ Department of Biostatistics, University of Washington, Seattle, Washington.
³⁸ Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain.
³⁹ ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
⁴⁰ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁴¹ Department of Clinical Sciences, Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona, Spain.
⁴² Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
⁴³ Department of Epidemiology, University of Washington, Seattle, Washington.
⁴⁴ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
⁴⁵ Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
⁴⁶ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
⁴⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
⁴⁸ Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
⁴⁹ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

^# Contributed equally.

PMID: 38252034
PMCID: PMC10990777
DOI: 10.1158/1055-9965.EPI-23-0600

Abstract

Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88.

Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases).

Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066).

Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available.

Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

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Conflict of interest statement

Conflict of Interest: Andrew T Chan has no COI related to this manuscript. For research unrelated to this manuscript, he has grant support from Pfizer Inc., Zoe Ltd, Freenome and consulting fees from Pfizer Inc, Boheringer Ingelheim, and Bayer Pharma AG. Marios Giannakis has no COI related to this manuscript; unrelated he has research funding from Janssen. All other authors have nothing to disclose.

References

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Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature

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Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature

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Conflict of interest statement

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