不同白细胞比例与女性乳腺癌发病风险
既往研究发现，女性白细胞总数增加可能与乳腺癌发病风险增加相关。不过，不同白细胞比例与乳腺癌发病风险的相关性尚不明确。
2020年1月17日，《美国医学会杂志》网络开放版在线发表美国国家环境卫生科学研究所的姐妹研究亚组分析报告，探讨了外周血液循环不同白细胞比例与乳腺癌发病风险的相关性。
姐妹研究于2003～2009年从美国和波多黎各自由邦入组姐妹已被诊断为乳腺癌、自己尚未发生乳腺癌女性50884例。本研究于2014年7月从整个姐妹研究队列选择非西班牙裔白人女性2774例（平均年龄56.6±8.8岁）采集外周血液样本，测量全血DNA甲基化值，并对甲基化值进行反卷积，推算6种白细胞亚型（B淋巴细胞、自然杀伤细胞、CD8阳性T淋巴细胞、CD4阳性T淋巴细胞、单核细胞、粒细胞）的比例，并随访至2016年10月。2019年4月对数据进行分析，主要结局为女性乳腺癌的发生。将白细胞亚型比例按其人群中位数二等分，并通过多因素比例风险回归模型分析与乳腺癌的相关性。
结果，平均随访6.0±3.2年期间，其中1570例发生乳腺癌，其余1204例未发生乳腺癌。
B淋巴细胞比例较高与较低的女性相比：
乳腺癌发病风险高1.17倍（风险比：1.17，95%置信区间：1.01～1.36，P=0.04）。
采血时未绝经者乳腺癌发病风险高1.38倍（风险比：1.38，95%置信区间：1.05～1.82，P=0.02）
采血后≥4年乳腺癌发病风险高1.38倍（风险比：1.38，95%置信区间：1.15～1.67，P=0.001）
单核细胞比例较高与较低的女性相比：
乳腺癌发病风险低25%（风险比：0.75，95%置信区间：0.57～0.99，P=0.05）
采血后<1年乳腺癌发病风险低38%（风险比：0.62，95%置信区间：0.43～0.89，P=0.01）
因此，该研究结果表明，外周血液循环白细胞比例改变可能早于乳腺癌临床诊断，并且可能是乳腺癌发病风险的时间相关指标，尤其对于绝经前女性。
对此，旧金山加利福尼亚大学（俗称：加州大学旧金山分校）发表特邀评论：细胞DNA甲基化测定能否作为乳腺癌的生物学预测标志？全文如下。
JAMA Netw Open. 2020 Jan 17;3(1):e1919536.
Prediagnostic Immune Cell Profiles and Breast Cancer.
Jacob K. Kresovich; Katie M. O'Brien; Zongli Xu; Clarice R. Weinberg; Dale P. Sandler; Jack A. Taylor.
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
This case-cohort study examines the associations between proportions of circulating leukocyte subtypes and the risk of breast cancer.
QUESTION: Is there an association between specific subtypes of circulating leukocytes and the risk of breast cancer?
FINDINGS: In this case-cohort study of 2774 women, lower proportions of circulating monocytes were associated with a higher risk of breast cancer within 1 year of the blood collection, whereas higher proportions of circulating B cells were associated with a higher risk of breast cancer 4 or more years later.
MEANING: Shifts in circulating leukocyte profiles appear to precede a breast cancer diagnosis and may serve as markers of time-dependent breast cancer risk.
IMPORTANCE: Higher overall leukocyte counts in women may be associated with increased risk of breast cancer, but the association of specific leukocyte subtypes with breast cancer risk remains unknown.
OBJECTIVE: To determine associations between circulating leukocyte subtypes and risk of breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: Between 2003 and 2009, the Sister Study enrolled 50884 women who had a sister previously diagnosed with breast cancer but were themselves breast cancer free. A case-cohort subsample was selected in July 2014 from the full Sister Study cohort. Blood samples were obtained at baseline, and women were followed up through October 2016. Data analysis was performed in April 2019.
MAIN OUTCOMES AND MEASURES: The main outcome was the development of breast cancer in women. Whole-blood DNA methylation was measured, and methylation values were deconvoluted using the Houseman method to estimate proportions of 6 leukocyte subtypes (B cells, natural killer cells, CD8+ and CD4+ T cells, monocytes, and granulocytes). Leukocyte subtype proportions were dichotomized at their population median value, and Cox proportional hazard models were used to estimate associations with breast cancer.
RESULTS: Among 2774 non-Hispanic white women included in the analysis (mean [SD] age at enrollment, 56.6 [8.8] years), 1295 women were randomly selected from the full cohort (of whom 91 developed breast cancer) along with an additional 1479 women who developed breast cancer during follow-up (mean [SD] time to diagnosis, 3.9 [2.2] years). Circulating proportions of B cells were positively associated with later breast cancer (hazard ratio [HR], 1.17; 95% CI, 1.01-1.36; P = .04). Among women who were premenopausal at blood collection, the association between B cells and breast cancer was significant (HR, 1.38; 95% CI, 1.05-1.82; P = .02), and an inverse association for circulating proportions of monocytes was found (HR, 0.75; 95% CI, 0.57-0.99; P = .05). Among all women, associations between leukocyte subtypes and breast cancer were time dependent: higher monocyte proportions were associated with decreased near-term risk (within 1 year of blood collection, HR, 0.62; 95% CI, 0.43-0.89; P = .01), whereas higher B cell proportions were associated with increased risk 4 or more years after blood collection (HR, 1.38; 95% CI, 1.15-1.67; P = .001).
CONCLUSIONS AND RELEVANCE: Circulating leukocyte profiles may be altered before clinical diagnoses of breast cancer and may be time-dependent markers for breast cancer risk, particularly among premenopausal women.
DOI: 10.1001/jamanetworkopen.2019.19536
JAMA Netw Open. 2020 Jan 17;3(1):e1919568.
Could Methylation Cytometry Be a Predictive Biomarker of Breast Cancer?
John K. Wiencke.
University of California, San Francisco.
DOI: 10.1001/jamanetworkopen.2019.19568