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Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women
  1. David Limsui1,
  2. Robert A Vierkant2,
  3. Lori S Tillmans3,
  4. Alice H Wang2,
  5. Daniel J Weisenberger4,
  6. Peter W Laird4,
  7. Charles F Lynch5,
  8. Kristin E Anderson6,
  9. Amy J French3,
  10. Robert W Haile7,
  11. Lisa J Harnack8,
  12. John D Potter9,
  13. Susan L Slager2,
  14. Thomas C Smyrk3,
  15. Stephen N Thibodeau3,
  16. James R Cerhan10,
  17. Paul J Limburg1
  1. 1Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA
  2. 2Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, Minnesota, USA
  3. 3Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota, USA
  4. 4USC Epigenome Center, Norris Comprehensive Cancer Center, Los Angeles, California, USA
  5. 5Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA
  6. 6Department of Epidemiology, University of Minnesota, Minneapolis, Minnesota, USA
  7. 7Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, California, USA
  8. 8Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
  9. 9Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  10. 10Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Paul J Limburg, 200 First Street SW, Rochester, MN 55905, USA; limburg.paul{at}


Background Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive.

Objectives To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women's Health Study of older women.

Methods Exposure data were collected from Iowa Women's Health Study participants (55–69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs.

Results PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes.

Conclusions In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.

  • Postmenopausal hormone therapy
  • colorectal cancer
  • cohort study
  • molecular epidemiology
  • microsatellite instability
  • CpG island methylator phenotype
  • BRAF
  • KRAS
  • cancer epidemiology
  • cancer genetics
  • epidemiology
  • statistics
  • epidemiology
  • gastrointestinal neoplasia
  • pancreatic cancer
  • epidemiology
  • cancer prevention
  • cancer epidemiology
  • chemoprevention
  • Helicobacter pylori
  • acid-related diseases
  • non-ulcer dyspepsia
  • genetic polymorphisms
  • gastric neoplasia

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  • Funding This work was supported by grant funding from the National Institutes of Health (USA), including R01 CA107333 (Limburg, PI). Dr Weisenberger's participation was also partially supported by seed funding from the American Cancer Society.

  • Competing interests Dr Weisenberger holds patents and receives royalties from the University of Southern California (outside of the submitted work). Dr Laird serves on the Scientific Advisory Board and as a Consultant to Epigenomics, AG., and also receives financial support from patents and royalties related to methylation technology from this group (outside of the submitted work). Dr Limburg also receives support for his research from Olympus America, BENEO-Orafti Group, Bayer Healthcare, Fujinon, Boston Scientific, and Astra Zeneca (outside of the submitted work). He is listed as a co-inventor on US patent 5891651, served as a consultant for Genomic Health, Inc. from 8/12/08-4/19/10, and Mayo Clinic has licensed Dr Limburg's intellectual property to Exact Sciences, for which he and Mayo Clinic have contractual rights to receive royalties(outside of the submitted work).

  • Ethics approval This study was reviewed and approved by the institutional review boards for human research of the University of Iowa, University of Minnesota and Mayo Clinic.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data from this study will be made available upon request to the Corresponding Author (Dr Limburg), in accordance with relevant guidelines from the funding agency.

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