Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk

  • Yu Tian
  • , Yi Lin
  • , Conghui Qu
  • , Volker Arndt
  • , James W. Baurley
  • , Sonja I. Berndt
  • , Stephanie A. Bien
  • , D. Timothy Bishop
  • , Hermann Brenner
  • , Daniel D. Buchanan
  • , Arif Budiarto
  • , Peter T. Campbell
  • , Robert Carreras-Torres
  • , Graham Casey
  • , Andrew T. Chan
  • , Rui Chen
  • , Xuechen Chen
  • , David V. Conti
  • , Virginia Díez-Obrero
  • , Niki Dimou
    • David A. Drew, Jane C. Figueiredo, Steven Gallinger, Graham G. Giles, Stephen B. Gruber, Marc J. Gunter, Sophia Harlid, Tabitha A. Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R. Huyghe, Mark A. Jenkins, Kristina M. Jordahl, Amit D. Joshi, Temitope O. Keku, Eric Kawaguchi, Andre E. Kim, Anshul Kundaje, Susanna C. Larsson, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Victor Moreno, John Morrison, Neil Murphy, Hongmei Nan, Rami Nassir, Polly A. Newcomb, Mireia Obón-Santacana, Shuji Ogino, Jennifer Ose, Bens Pardamean, Andrew J. Pellatt, Anita R. Peoples, Elizabeth A. Platz, John D. Potter, Ross L. Prentice, Gad Rennert, Edward A. Ruiz-Narvaez, Lori C. Sakoda, Robert E. Schoen, Anna Shcherbina, Mariana C. Stern, Yu-Ru Su, Stephen N. Thibodeau, Duncan C. Thomas, Konstantinos K. Tsilidis, Franzel J. B. van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Emily White, Alicja Wolk, Michael O. Woods, Anna H. Wu, Ulrike Peters, W. James Gauderman, Li Hsu, Jenny Chang-Claude

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10−8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%–4.0%) vs 6.1% (5.7%–6.5%) (difference 2.4%, P-value = 1.83 × 10−14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%–1.8%) vs 2.2% (1.9%–2.4%) (difference 0.6%, P-value = 1.01 × 10−3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
Original languageEnglish
Pages (from-to)1687-1696
JournalBritish Journal of Cancer
Volume130
Issue number10
DOIs
Publication statusPublished - 1 Jun 2024
Externally publishedYes

Funding

We thank Prof. Dr. Cornelia M. Ulrich (Huntsman Cancer Institute; Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA) for providing a further perspective to polish our manuscript. CCFR : The Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff, and the financial support from the U.S. National Cancer Institute, without which this important registry would not exist. The authors would like to thank the study participants and staff of the Seattle Colon Cancer Family Registry and the Hormones and Colon Cancer study (CORE Studies). CLUE II : We thank the participants of Clue II and appreciate the continued efforts of the staff at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the Clue II Cohort Study. Cancer data was provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund. The collection and availability of cancer registry data is also supported by the Cooperative Agreement NU58DP006333, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. CPS-II : The authors express sincere appreciation to all Cancer Prevention Study-II participants, and to each member of the study and biospecimen management group. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute’s Surveillance Epidemiology and End Results Program. The authors assume full responsibility for all analyses and interpretation of results. The views expressed here are those of the authors and do not necessarily represent the American Cancer Society or the American Cancer Society – Cancer Action Network. DACHS : We thank all participants and cooperating clinicians, and everyone who provided excellent technical assistance. EPIC : Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Harvard cohorts : The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. We acknowledge Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital as home of the NHS. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming. The authors assume full responsibility for analyses and interpretation of these data. Kentucky : We would like to acknowledge the staff at the Kentucky Cancer Registry. LCCS : We acknowledge the contributions of Jennifer Barrett, Robin Waxman, Gillian Smith and Emma Northwood in conducting this study. NCCCS I & II : We would like to thank the study participants, and the NC Colorectal Cancer Study staff. PLCO : The authors thank the PLCO Cancer Screening Trial screening center investigators and the staff from Information Management Services Inc and Westat Inc. Most importantly, we thank the study participants for their contributions that made this study possible. Cancer incidence data have been provided by the District of Columbia Cancer Registry, Georgia Cancer Registry, Hawaii Cancer Registry, Minnesota Cancer Surveillance System, Missouri Cancer Registry, Nevada Central Cancer Registry, Pennsylvania Cancer Registry, Texas Cancer Registry, Virginia Cancer Registry, and Wisconsin Cancer Reporting System. All are supported in part by funds from the Center for Disease Control and Prevention, National Program for Central Registries, local states or by the National Cancer Institute, Surveillance, Epidemiology, and End Results program. The results reported here and the conclusions derived are the sole responsibility of the authors. WHI : The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf .

FundersFunder number
Centers for Disease Control and Prevention
State of Maryland
Maryland Department of Health
National Cancer Institute’s Surveillance Epidemiology and End Results Program
National Cancer Institute
Maryland Cancer Registry
Maryland Cigarette Restitution FundNU58DP006333
National Health and Medical Research Council509348, 209057

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