Jung Su Yon, Papp Jeanette C, Sobel Eric M, Pellegrini Matteo, Yu Herbert, Zhang Zuo-Feng
Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, 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.
Front Oncol. 2021 Feb 3;10:630994. doi: 10.3389/fonc.2020.630994. eCollection 2020.
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.
影响乳腺癌风险的免疫相关病因途径尚未完全明确，可能会受到生活方式或反向因果关系的干扰。我们采用孟德尔随机化（MR）方法，研究绝经后女性中基因决定的C反应蛋白（CRP）浓度升高与原发性浸润性乳腺癌风险之间的潜在因果关系。
我们使用了来自女性健康倡议数据库基因型和表型研究的10179名女性的个体水平数据，其中包括537名患乳腺癌的女性，该数据库由五项全基因组关联（GWA）研究组成。我们检测了先前与CRP相关的61个GWA单核苷酸多态性（SNP）。我们采用加权/惩罚加权中位数和MR基因-环境相互作用方法，这些方法在一定程度上允许工具无效，并减弱异常SNP的异质性估计。
在生活方式分层分析中，基因决定的CRP升高降低了仅使用外源性雌激素、雌激素+孕激素以及既往口服避孕药（OC）使用者患乳腺癌的风险，但仅在相对短期使用者（<5年）中。仅使用雌激素≥5年的使用者患乳腺癌风险因CRP降低呈剂量反应关系，而既往使用OC≥5年的使用者患癌风险因CRP升高。此外，基因预测的CRP与激素受体阳性或人表皮生长因子受体2阴性乳腺癌风险增加密切相关。
我们的研究结果可能为与乳腺癌风险相关的免疫相关分子途径提供新证据，并提示CRP在预测特定癌症亚型方面的潜在临床应用。我们的研究结果表明，针对CRP炎症标志物的潜在干预措施可降低乳腺癌风险。
