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

• Published in: Frontiers in oncology Vol. 10; p. 630994
• Main Authors: Jung, Su Yon, Papp, Jeanette C., Sobel, Eric M., Pellegrini, Matteo, Yu, Herbert, Zhang, Zuo-Feng
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 03.02.2021
• Subjects: breast cancer subtypes by hormone receptor and HER2/neu; exogenous estrogen; genetically driven C-reactive protein; Mendelian randomization; obesity; Oncology; breast cancer subtypes by hormone receptor and HER2/neu; Mendelian randomization; genetically driven C-reactive protein; exogenous estrogen; obesity
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2020.630994

Immune-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. We 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. In 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. Our 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.