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

Su Yon Jung; Jeanette C Papp; Eric M Sobel; Matteo Pellegrini; Herbert Yu; Zuo-Feng Zhang

doi:10.3389/fonc.2020.630994

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

Front Oncol. 2021 Feb 3:10:630994. doi: 10.3389/fonc.2020.630994. eCollection 2020.

Authors

Su Yon Jung¹, Jeanette C Papp², Eric M Sobel^{2

3}, Matteo Pellegrini⁴, Herbert Yu⁵, Zuo-Feng Zhang^{6

7}

Affiliations

¹ Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California, Los Angeles, Los Angeles, CA, United States.
² Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
³ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
⁴ Department of Molecular, Cell and Developmental Biology, Life Sciences Division, University of California, Los Angeles, Los Angeles, CA, United States.
⁵ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States.
⁶ Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, United States.
⁷ Center for Human Nutrition, David Geffen School of Medicine, University of California, Los Angeles, CA, United States.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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

Abstract

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