PMID- 36790512 OWN - NLM STAT- MEDLINE DCOM- 20230419 LR - 20240502 IS - 1573-7225 (Electronic) IS - 0957-5243 (Print) IS - 0957-5243 (Linking) VI - 34 IP - 5 DP - 2023 May TI - mTOR pathway candidate genes and obesity interaction on breast cancer risk in black women from the Women's Circle of Health Study. PG - 431-447 LID - 10.1007/s10552-022-01657-9 [doi] AB - BACKGROUND: Obesity is known to stimulate the mammalian target of rapamycin (mTOR) signaling pathway and both obesity and the mTOR signaling pathway are implicated in breast carcinogenesis. We investigated potential gene-environment interactions between mTOR pathway genes and obesity in relation to breast cancer risk among Black women. METHODS: The study included 1,655 Black women (821 incident breast cancer cases and 834 controls) from the Women's Circle of Health Study (WCHS). Obesity measures including body mass index (BMI); central obesity i.e., waist circumference (WC) and waist/hip ratio (WHR); and body fat distribution (fat mass, fat mass index and percent body fat) were obtained by trained research staff. We examined the associations of 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with breast cancer risk using multivariable logistic regression. We next examined interactions between these SNPs and measures of obesity using Wald test with 2-way interaction term. RESULTS: The variant allele of BRAF (rs114729114 C > T) was associated with an increase in overall breast cancer risk [odds ratio (OR) = 1.81, 95% confidence interval (CI) 1.10-2.99, for each copy of the T allele] and the risk of estrogen receptor (ER)-defined subtypes (ER+ tumors: OR = 1.83, 95% CI 1.04,3.29, for each copy of the T allele; ER- tumors OR = 2.14, 95% CI 1.03,4.45, for each copy of the T allele). Genetic variants in AKT, AKT1, PGF, PRKAG2, RAPTOR, TSC2 showed suggestive associations with overall breast cancer risk and the risk of, ER+ and ER- tumors (range of p-values = 0.040-0.097). We also found interactions of several of the SNPs with BMI, WHR, WC, fat mass, fat mass index and percent body fat in relation to breast cancer risk. These associations and interactions, however, became nonsignificant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION: We found associations between mTOR genetic variants and breast cancer risk as well as gene and body fatness interactions in relation to breast cancer risk. However, these associations and interactions became nonsignificant after correction for multiple testing. Future studies with larger sample sizes are required to confirm and validate these findings. CI - (c) 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG. FAU - Ilozumba, Mmadili N AU - Ilozumba MN AUID- ORCID: 0000-0002-9928-3711 AD - Department of Epidemiology, University of Florida, Gainesville, FL, USA. Mmadili.Ilozumba@hci.utah.edu. AD - Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA. Mmadili.Ilozumba@hci.utah.edu. FAU - Yaghjyan, Lusine AU - Yaghjyan L AD - Department of Epidemiology, University of Florida, Gainesville, FL, USA. FAU - Datta, Susmita AU - Datta S AD - Department of Biostatistics, University of Florida, Gainesville, FL, USA. FAU - Zhao, Jinying AU - Zhao J AD - Department of Epidemiology, University of Florida, Gainesville, FL, USA. FAU - Hong, Chi-Chen AU - Hong CC AD - Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. FAU - Lunetta, Kathryn L AU - Lunetta KL AD - Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. FAU - Zirpoli, Gary AU - Zirpoli G AD - Slone Epidemiology Center, Boston University, Boston, MA, USA. FAU - Bandera, Elisa V AU - Bandera EV AD - Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. FAU - Palmer, Julie R AU - Palmer JR AD - Slone Epidemiology Center, Boston University, Boston, MA, USA. FAU - Yao, Song AU - Yao S AD - Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. FAU - Ambrosone, Christine B AU - Ambrosone CB AD - Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. FAU - Cheng, Ting-Yuan David AU - Cheng TD AD - Department of Epidemiology, University of Florida, Gainesville, FL, USA. ting-yuan.cheng@osumc.edu. AD - Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. ting-yuan.cheng@osumc.edu. AD - Division of Cancer Prevention and Control, Department of Internal Medicine, The Ohio State University, Suite 525, 1590 North High Street, Columbus, OH, 43201, USA. ting-yuan.cheng@osumc.edu. LA - eng GR - P30 CA016056/CA/NCI NIH HHS/United States GR - P01 CA151135/CA/NCI NIH HHS/United States GR - R37 CA248371/CA/NCI NIH HHS/United States GR - R01 CA185623/CA/NCI NIH HHS/United States GR - R01 CA100598/CA/NCI NIH HHS/United States GR - R01 CA098663/CA/NCI NIH HHS/United States GR - K07 CA201334/CA/NCI NIH HHS/United States GR - P30 CA072720/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20230215 PL - Netherlands TA - Cancer Causes Control JT - Cancer causes & control : CCC JID - 9100846 RN - EC 2.7.1.1 (MTOR protein, human) RN - 0 (Receptors, Estrogen) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Female MH - Humans MH - *Black or African American/genetics/statistics & numerical data MH - Body Mass Index MH - *Breast Neoplasms/epidemiology/ethnology/genetics/metabolism MH - Gene-Environment Interaction MH - *Obesity/epidemiology/ethnology/genetics/metabolism MH - Polymorphism, Single Nucleotide MH - Receptors, Estrogen/metabolism MH - Risk MH - Risk Factors MH - Signal Transduction MH - TOR Serine-Threonine Kinases/genetics PMC - PMC10695180 MID - NIHMS1944111 OTO - NOTNLM OT - Black women OT - Breast cancer OT - Effect modification OT - Obesity OT - mTOR pathway COIS- Statements and Declaration Competing interests The authors have no relevant financial or non-financial interests to disclose. EDAT- 2023/02/16 06:00 MHDA- 2023/04/18 06:42 PMCR- 2024/05/01 CRDT- 2023/02/15 11:15 PHST- 2022/07/05 00:00 [received] PHST- 2022/11/11 00:00 [accepted] PHST- 2023/04/18 06:42 [medline] PHST- 2023/02/16 06:00 [pubmed] PHST- 2023/02/15 11:15 [entrez] PHST- 2024/05/01 00:00 [pmc-release] AID - 10.1007/s10552-022-01657-9 [pii] AID - 10.1007/s10552-022-01657-9 [doi] PST - ppublish SO - Cancer Causes Control. 2023 May;34(5):431-447. doi: 10.1007/s10552-022-01657-9. Epub 2023 Feb 15.