PMID- 29256014 OWN - NLM STAT- MEDLINE DCOM- 20190319 LR - 20191227 IS - 1573-7217 (Electronic) IS - 0167-6806 (Print) IS - 0167-6806 (Linking) VI - 168 IP - 2 DP - 2018 Apr TI - Genetic variation in TNFalpha, PPARgamma, and IRS-1 genes, and their association with breast-cancer survival in the HEAL cohort. PG - 567-576 LID - 10.1007/s10549-017-4621-x [doi] AB - PURPOSE: Tumor necrosis factor-alpha (TNF-alpha), peroxisome proliferator-activated receptor-gamma (PPARgamma), and insulin receptor substrate-1 (IRS-1) are associated with obesity, insulin resistance, and inflammation. Few data exist on associations between polymorphisms in these genes and mortality in breast cancer survivors. METHODS: We investigated associations between TNF-alpha (-308)G > A (rs1800629); PPARgamma Pro(12)Ala (rs1801282); and IRS-1 Gly(972)Arg (rs1801278) polymorphisms and anthropometric variables, circulating levels of previously measured biomarkers, and tumor characteristics in 553 women enrolled in the Health, Eating, Activity, and Lifestyle Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer between 1995 and 1999 (median follow-up 14.7 years). Using Cox proportional hazards models adjusted for possible confounders, we evaluated associations between these polymorphisms and mortality. RESULTS: Carriers of the PPARgamma variant allele had statistically significantly lower rates of type 2 diabetes (P = 0.04), lower BMI (P = 0.01), and HOMA scores [P = 0.004; non-Hispanic White (NHWs) only]; carriers of the TNF-alpha variant A allele had higher serum glucose (P = 0.004, NHW only); and the IRS-1 variant was associated with higher leptin levels (P = 0.003, Hispanics only). There were no associations between any of the polymorphisms and tumor characteristics. Among 141 deaths, 62 were due to breast cancer. Carriers of the TNF-alpha-variant A allele had a decreased risk of breast-cancer-specific mortality [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.10-0.83] and all-cause mortality (HR 0.51; 95% CI 0.28-0.91). CONCLUSIONS: Neither the PPARgamma nor the IRS-1 polymorphism was associated with mortality outcome. The TNF-alpha (-308) G > A polymorphism was associated with reduced breast-cancer-specific and all-cause mortality. FAU - Duggan, Catherine AU - Duggan C AUID- ORCID: 0000-0001-7369-4021 AD - Epidemiology Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. cduggan@fhcrc.org. FAU - Baumgartner, Richard N AU - Baumgartner RN AD - Department of Epidemiology & Population Health, University of Louisville, Louisville, KY, USA. FAU - Baumgartner, Kathy B AU - Baumgartner KB AD - Department of Epidemiology & Population Health, University of Louisville, Louisville, KY, USA. FAU - Bernstein, Leslie AU - Bernstein L AD - Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA. FAU - George, Stephanie AU - George S AD - Office of Disease Prevention, National Institutes of Health, Rockville, MD, USA. FAU - Ballard, Rachel AU - Ballard R AD - Office of Disease Prevention, National Institutes of Health, Rockville, MD, USA. FAU - Neuhouser, Marian L AU - Neuhouser ML AD - Epidemiology Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. FAU - McTiernan, Anne AU - McTiernan A AD - Epidemiology Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. AD - Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA. LA - eng GR - R25-CA94880/NH/NIH HHS/United States GR - BCRF-16-106/Breast Cancer Research Foundation/ GR - N01 PC067010/PC/NCI NIH HHS/United States GR - 050Q-8709-S1528/California Department of Public Health/ GR - R25 CA094880/CA/NCI NIH HHS/United States GR - M01 RR000037/RR/NCRR NIH HHS/United States GR - N01-PC-67010/NH/NIH HHS/United States GR - N01-HD-3-3175/NH/NIH HHS/United States GR - N01-CN-05228/NH/NIH HHS/United States GR - U54 CA116848/CA/NCI NIH HHS/United States GR - N01 CN005228/CN/NCI NIH HHS/United States GR - U54-CA116847/NH/NIH HHS/United States GR - M01 RR000997/RR/NCRR NIH HHS/United States GR - N01-CN-75036-20/NH/NIH HHS/United States GR - U54 CA116847/CA/NCI NIH HHS/United States GR - NCRR M01-RR-0997/University of New Mexico/ PT - Journal Article DEP - 20171218 PL - Netherlands TA - Breast Cancer Res Treat JT - Breast cancer research and treatment JID - 8111104 RN - 0 (IRS1 protein, human) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (PPAR gamma) RN - 0 (PPARG protein, human) RN - 0 (TNF protein, human) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Aged MH - Breast Neoplasms/genetics/*mortality/pathology MH - Cancer Survivors/*statistics & numerical data MH - Female MH - Humans MH - Insulin Receptor Substrate Proteins/*genetics MH - Los Angeles/epidemiology MH - Middle Aged MH - Neoplasm Staging MH - New Mexico/epidemiology MH - PPAR gamma/*genetics MH - Polymorphism, Genetic MH - Prospective Studies MH - SEER Program/statistics & numerical data MH - Survival Analysis MH - Tumor Necrosis Factor-alpha/*genetics MH - Washington/epidemiology PMC - PMC5839976 MID - NIHMS928903 OTO - NOTNLM OT - All-cause mortality OT - PPARgamma IRS-1 TNF-alpha breast-cancer-specific mortality COIS- Conflict of Interest Statement: The authors declare that they have no conflict of interest. EDAT- 2017/12/20 06:00 MHDA- 2019/03/20 06:00 PMCR- 2019/04/01 CRDT- 2017/12/20 06:00 PHST- 2017/10/03 00:00 [received] PHST- 2017/12/08 00:00 [accepted] PHST- 2017/12/20 06:00 [pubmed] PHST- 2019/03/20 06:00 [medline] PHST- 2017/12/20 06:00 [entrez] PHST- 2019/04/01 00:00 [pmc-release] AID - 10.1007/s10549-017-4621-x [pii] AID - 10.1007/s10549-017-4621-x [doi] PST - ppublish SO - Breast Cancer Res Treat. 2018 Apr;168(2):567-576. doi: 10.1007/s10549-017-4621-x. Epub 2017 Dec 18.