Genetically Predicted C-Reactive Protein Associated With Postmenopausal Breast Cancer Risk: Interrelation With Estrogen and Cancer Molecular Subtypes Using Mendelian Randomization

Frontiers in Oncology

Herbert Yu¹  Zuo-Feng Zhang²  Eric M. Sobel³  Jeanette C. Papp⁵  Matteo Pellegrini⁶  Su Yon Jung⁷ 

[1] Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States;Center for Human Nutrition, David Geffen School of Medicine, University of California, Los Angeles, CA, United States;Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States;Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, United States;Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States;Department of Molecular, Cell and Developmental Biology, Life Sciences Division, University of California, Los Angeles, Los Angeles, CA, United States;Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California, Los Angeles, Los Angeles, CA, United States;

关键词: genetically driven C-reactive protein;    Mendelian randomization;    obesity;    exogenous estrogen;    breast cancer subtypes by hormone receptor and HER2/neu;   

DOI  :  10.3389/fonc.2020.630994

来源: DOAJ

【 摘 要 】

BackgroundImmune-related etiologic pathways that influence breast cancer risk are incompletely understood and may be confounded by lifestyles or reverse causality. Using a Mendelian randomization (MR) approach, we investigated the potential causal relationship between genetically elevated C-reactive protein (CRP) concentrations and primary invasive breast cancer risk in postmenopausal women.MethodsWe used individual-level data obtained from 10,179 women, including 537 who developed breast cancer, from the Women’s Health Initiative Database for Genotypes and Phenotypes Study, which consists of five genome-wide association (GWA) studies. We examined 61 GWA single-nucleotide polymorphisms (SNPs) previously associated with CRP. We employed weighted/penalized weighted–medians and MR gene–environment interactions that allow instruments’ invalidity to some extent and attenuate the heterogeneous estimates of outlying SNPs.ResultsIn lifestyle-stratification analyses, genetically elevated CRP decreased risk for breast cancer in exogenous estrogen-only, estrogen + progestin, and past oral contraceptive (OC) users, but only among relatively short-term users (<5 years). Estrogen-only users for ≥5 years had more profound CRP-decreased breast cancer risk in dose–response fashion, whereas past OC users for ≥5 years had CRP-increased cancer risk. Also, genetically predicted CRP was strongly associated with increased risk for hormone-receptor positive or human epidermal growth factor receptor-2 negative breast cancer.ConclusionsOur findings may provide novel evidence on the immune-related molecular pathways linking to breast cancer risk and suggest potential clinical use of CRP to predict the specific cancer subtypes. Our findings suggest potential interventions targeting CRP–inflammatory markers to reduce breast cancer risk.

【 授权许可】

Unknown