Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk
Authors: Tian Yu , Lin Yi , Qu Conghui , Arndt Volker , Baurley James W. , Berndt Sonja I. , Bien Stephanie A. , Bishop D. Timothy , Brenner Hermann , Buchanan Daniel D. , Budiarto Arif , Campbell Peter T. , Carreras-Torres Robert , Casey Graham , Chan Andrew T. , Chen Rui , Chen Xuechen , Conti David V. , Díez-Obrero Virginia , Dimou Niki , Drew David A. , Figueiredo Jane C. , Gallinger Steven , Giles Graham G. , Gruber Stephen B. , Gunter Marc J. , Harlid Sophia , Harrison Tabitha A. , Hidaka Akihisa , Hoffmeister Michael , Huyghe Jeroen R. , Jenkins Mark A. , Jordahl Kristina M. , Joshi Amit D. , Keku Temitope O. , Kawaguchi Eric , Kim Andre E. , Kundaje Anshul , Larsson Susanna C. , Marchand Loic Le , Lewinger Juan Pablo , Li Li , Moreno Victor , Morrison John , Murphy Neil , Nan Hongmei , Nassir Rami , Newcomb Polly A. , Obón-Santacana Mireia , Ogino Shuji , Ose Jennifer , Pardamean Bens , Pellatt Andrew J. , Peoples Anita R. , Platz Elizabeth A. , Potter John D. , Prentice Ross L. , Rennert Gad , Ruiz-Narvaez Edward A. , Sakoda Lori C. , Schoen Robert E. , Shcherbina Anna , Stern Mariana C. , Su Yu-Ru , Thibodeau Stephen N. , Thomas Duncan C. , Tsilidis Konstantinos K. , van Duijnhoven Franzel J. B. , Van Guelpen Bethany , Visvanathan Kala , White Emily , Wolk Alicja , Woods Michael O. , Wu Anna H. , Peters Ulrike , Gauderman W. James , Hsu Li , Chang-Claude Jenny 
Published: April 2024

AbstractBackgroundMenopausal 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.MethodsWe 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.ResultsThe 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.ConclusionsMHT 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.