Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk. (5th May 2022)

• Record Type: Journal Article
• Authors: Tian, Yu; Kim, Andre E; Bien, Stephanie A; Lin, Yi; Qu, Conghui; Harrison, Tabitha A; Carreras-Torres, Robert; Díez-Obrero, Virginia; Dimou, Niki; Drew, David A; Hidaka, Akihisa; Huyghe, Jeroen R; Jordahl, Kristina M; Morrison, John; Murphy, Neil; Obón-Santacana, Mireia; Ulrich, Cornelia M; Ose, Jennifer; Peoples, Anita R; Ruiz-Narvaez, Edward A; Shcherbina, Anna; Stern, Mariana C; Su, Yu-Ru; van Duijnhoven, Franzel J B; Arndt, Volker; Baurley, James W; Berndt, Sonja I; Bishop, D Timothy; Brenner, Hermann; Buchanan, Daniel D; Chan, Andrew T; Figueiredo, Jane C; Gallinger, Steven; Gruber, Stephen B; Harlid, Sophia; Hoffmeister, Michael; Jenkins, Mark A; Joshi, Amit D; Keku, Temitope O; Larsson, Susanna C; Le Marchand, Loic; Li, Li; Giles, Graham G; Milne, Roger L; Nan, Hongmei; Nassir, Rami; Ogino, Shuji; Budiarto, Arif; Platz, Elizabeth A; Potter, John D; Prentice, Ross L; Rennert, Gad; Sakoda, Lori C; Schoen, Robert E; Slattery, Martha L; Thibodeau, Stephen N; Van Guelpen, Bethany; Visvanathan, Kala; White, Emily; Wolk, Alicja; Woods, Michael O; Wu, Anna H; Campbell, Peter T; Casey, Graham; Conti, David V; Gunter, Marc J; Kundaje, Anshul; Lewinger, Juan Pablo; Moreno, Victor; Newcomb, Polly A; Pardamean, Bens; Thomas, Duncan C; Tsilidis, Konstantinos K; Peters, Ulrike; Gauderman, W James; Hsu, Li; Chang-Claude, Jenny;
• Is Part Of: Journal of the National Cancer Institute. Volume 114:Number 8(2022)
• Page Start: 1135
• Page End: 1148
• Publication Date: 2022-05-05
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; 616.994
• DOI: 10.1093/jnci/djac094
• Languages: English
• ISSNs: 0027-8874

Abstract

Abstract: Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10 −4 ). Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.