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Epidemiologic factors in relation to colorectal cancer risk and survival by genotoxic colibactin mutational signature.

About this Publication
Title
Epidemiologic factors in relation to colorectal cancer risk and survival by genotoxic colibactin mutational signature.
Pubmed ID
38252034 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Cancer Epidemiol Biomarkers Prev. 2024 Jan 22
Authors
Thomas CE, Georgeson P, Qu C, Steinfelder RS, Buchanan DD, Song M, Harrison TA, Um CY, Hullar MA, Jenkins MA, Van Guelpen B, Lynch BM, Melaku YA, Huyghe JR, Aglago EK, Berndt SI, Boardman LA, Campbell PT, Cao Y, Chan AT, ...show more Drew DA, Figueiredo JC, French AJ, Giannakis M, Goode EL, Gruber SB, Gsur A, Gunter MJ, Hoffmeister M, Hsu L, Huang WY, Moreno V, Murphy N, Newcomb PA, Newton CC, Nowak JA, Obón-Santacana M, Ogino S, Sun W, Toland AE, Trinh QM, Ugai T, Zaidi SH, Peters U, Phipps AI
Affiliations
  • Fred Hutchinson Cancer Center, Seattle, WA, United States.
  • University of Melbourne, Melbourne, Australia.
  • Fred Hutchinson Cancer Center, United States.
  • University of Melbourne, Parkville, Victoria, Australia.
  • Harvard T.H. Chan School of Public Health, Boston, MA, United States.
  • Fred Hutchinson Cancer Center, Seattle, United States.
  • American Cancer Society, Kennesaw, GA, United States.
  • University of Melbourne, University of Melbourne, Victoria, Australia.
  • Umeå University, Umeå, Sweden.
  • Cancer Council Victoria, East Melbourne, Victoria, Australia.
...show more
  • Cancer Council Victoria, Melbourne, Australia.
  • Imperial College London, London, United Kingdom.
  • National Cancer Institute, Bethesda, MD, United States.
  • Mayo Clinic, Rochester, MN, United States.
  • Albert Einstein College of Medicine, Bronx, NY, United States.
  • Washington University in St. Louis, St Louis, Missouri, United States.
  • Massachusetts General Hospital, Boston, MA, United States.
  • University of Connecticut Health Center, Boston, MA, United States.
  • Cedars-Sinai Medical Center, Los Angeles, CA, United States.
  • Dana-Farber Cancer Institute, Boston, MA, United States.
  • Mayo Clinic College of Medicine, Rochester, MN, United States.
  • City Of Hope National Medical Center, Duarte, CA, United States.
  • Medical University of Vienna, Vienna, Austria.
  • International Agency For Research On Cancer, Lyon Cedex 08, France.
  • German Cancer Research Center, Heidelberg, Germany.
  • Catalan Institute of Oncology, Hopitalet de Llobregat, Barcelona, Spain.
  • International Agency For Research On Cancer, Lyon, France.
  • American Cancer Society, Atlanta, GA, United States.
  • Brigham and Women's Hospital, Boston, MA, United States.
  • Institut d'Investigació Biomédica de Bellvitge, Barcelona, Spain.
  • Fred Hutchinson Cancer Center, Seattle, Washington, United States.
  • The Ohio State University, Columbus, OH, United States.
  • Ontario Institute for Cancer Research, Toronto, Canada.
  • Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
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 (CRC) risk and survival differ 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 CRC risk by SBS88 were assessed using multinomial regression (N=4,308 cases, 14,192 controls; cohort-only cases N=1,911), and with CRC-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 CRC than SBS88-negative CRC [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 BMI, alcohol, and fruit intake with CRC risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse CRC-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 CRC risk or survival. Higher BMI may be associated with worse CRC-specific survival among those SBS88-positive, however validation is needed in samples with whole-genome or exome sequencing available.

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

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