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血浆脂联素水平与不同分子亚型乳腺癌发生风险的相关性研究

李佳昌, 易芳, 刁莎, 李佳圆

李佳昌, 易芳, 刁莎, 等. 血浆脂联素水平与不同分子亚型乳腺癌发生风险的相关性研究[J]. 四川大学学报（医学版）, 2019, 50(5): 708-713.
引用本文: 李佳昌, 易芳, 刁莎, 等. 血浆脂联素水平与不同分子亚型乳腺癌发生风险的相关性研究[J]. 四川大学学报（医学版）, 2019, 50(5): 708-713.
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LI Jia-chang, YI Fang, DIAO Sha, et al. Association Between Plasma Adiponectin and Risk of Breast Cancer by Molecular Subtypes[J]. Journal of Sichuan University (Medical Sciences), 2019, 50(5): 708-713.
Citation: LI Jia-chang, YI Fang, DIAO Sha, et al. Association Between Plasma Adiponectin and Risk of Breast Cancer by Molecular Subtypes[J]. Journal of Sichuan University (Medical Sciences), 2019, 50(5): 708-713.
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栏目: 论著

血浆脂联素水平与不同分子亚型乳腺癌发生风险的相关性研究

  • 四川大学华西公共卫生学院/四川大学华西第四医院 流行病与卫生统计学系 (成都 610041)

基金项目: 

国家自然科学基金 81874282

四川省科技厅项目 2017SZ0005

四川省医学会项目 S17050

详细信息
    通讯作者:

    李佳圆, E-mail: lijiayuan73@163.com

Association Between Plasma Adiponectin and Risk of Breast Cancer by Molecular Subtypes

  • Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China

More Information

摘要

    摘要
  • 摘要:
      目的  探讨血浆脂联素水平与不同分子亚型乳腺癌发生风险的相关性。
      方法  本研究采用病例对照设计，选择2014年4月至2015年5月经组织病理学诊断确诊的乳腺癌新发病例437例作为病例组，选择同期健康体检女性469例作为对照组。采用统一编制的结构化调查问卷收集研究对象基本信息并采集血样，采用酶联免疫吸附试验(ELASA)测定血浆脂联素浓度。按绝经状态分层后，采用方差分析比较对照组与不同分子亚型乳腺癌血浆脂联素水平的分布差异，并用无序多分类logistic回归分析血浆脂联素水平与不同分子分型乳腺癌发生风险的相关性。
      结果  乳腺癌患者中有310例Luminal型、83例HER-2过表达型和44例基底型。对照组血浆脂联素水平中位数(P25，P75)为14.85(9.69, 21.35) μg/mL；病例组上述各分子亚型血浆脂联素水平中位数(P25，P75)分别为11.74(8.15, 16.14) μg/mL、12.02(8.43, 16.96) μg/mL和12.67(8.25, 17.27) μg/mL，与对照组相比差异有统计学意义(P0.001)。无序多分类logistic回归显示，调整了混杂因素后，与对照组比，血浆脂联素水平越高，绝经前Luminal型乳腺癌发生风险越低(OR绝经前Luminal=0.50，95%CI：0.27~0.92，P趋势=0.001)，绝经后Luminal型和HER-2过表达型乳腺癌发生风险越低(OR绝经后Luminal=0.06，95%CI：0.02~0.23，P趋势 < 0.001；OR绝经后HER-2+=0.06，95%CI：0.01~0.62，P趋势=0.001)，其余亚组无统计学意义。
      结论  低血浆脂联素水平将导致绝经前、绝经后Luminal型和绝经后HER-2过表达型乳腺癌的发生风险增高。

     

    Abstract:
      Objective  To explore the relationships between plasma adiponectin levels and risk of breast cancer by molecular subtype.
      Methods  A case-control study including 437 histopathologic confirmed primary breast cancer cases and 469 healthy female controls was conducted between April 2014 and May 2015. Basic information of the participants were collected using a structured questionnaire. Blood samples were collected and the plasma adiponectin levels were measured by enzyme-linked immunosorbent assay (ELASA). Analysis of variance (ANOVA) was used to compare the differences of plasma adiponectin levels among the control group and the breast cancer groups with different molecular subtypes. Multinomial logistic regression was used to investigate the association between plasma adiponectin levels and risk of breast cancer by molecular subtypes. All the statistical analyses were stratified by menopausal status.
      Results  Among the 437 breast cancer cases, there were 310 Luminal breast cancer cases, 83 HER-2-enriched breast cancer cases and 44 basal-like breast cancer cases. The median (P25, P75) of plasma adiponectin level of the controls was 14.85 (9.69, 21.35) μg/mL. The medians (P25, P75) of plasma adiponectin levels of the cases were 11.74 (8.15, 16.14) μg/mL, 12.02(8.43, 16.96) μg/mL and 12.67(8.25, 17.27) μg/mL for Luminal, HER-2-enriched and basal-like subtype respectively, which were statistically different from the controls (P < 0.001). Multinomial logistic regression showed that, after adjustment for the confounders, the higher levels of plasma adiponectin were associated with the lower risks of pre-menopausal Luminal breast cancer (ORpre-menopausal Luminal=0.50, 95%CI: 0.27-0.92, Ptrend=0.001), post-menopausal Luminal breast cancer (ORpost-menopausal Luminal=0.06, 95%CI: 0.02-0.23, Ptrend < 0.001) and post-menopausal HER-2-enriched breast cancer (ORpost-menopausal HER-2-enriched=0.06, 95%CI: 0.01-0.62, Ptrend=0.001).
      Conclusion  Lower levels of plasma adiponectin may increase the risk of pre-menopausal and post-menopausal Luminal breast cancer and post-menopausal HER-2-enriched breast cancer.

     

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  • 乳腺癌是我国女性发病率最高的恶性肿瘤，2015年乳腺癌新发病例达26.86万[1]，已成为威胁我国女性健康的重大公共卫生问题之一。影响乳腺癌发病的危险因素多样，且由于不同分子亚型乳腺癌的内部异质性，其发病影响因素也存在差异[2]。脂联素是主要由白色脂肪组织分泌的脂肪因子，分为球型、全长型、低分子质量、中分子质量和高分子质量5种构型，通过与特定的受体结合发挥其生物学功能，包括抗细胞增殖、抗血管生成、调节胰岛素敏感等[3-4]。目前，大多数流行病学研究结果倾向于血浆脂联素浓度与乳腺癌的发生风险存在负相关[5-7]，但是这些研究均未考虑不同分子亚型乳腺癌间的异质性。因此，本研究采用病例对照研究设计，按照绝经状态分层后，分析血浆脂联素浓度对不同分子亚型乳腺癌发生风险的影响。

    1.   对象与方法

    1.1   研究对象

    序贯收集2014年4月至2015年5月在四川大学华西医院和四川省肿瘤医院经组织病理学诊断确诊的乳腺癌新发病例，纳入具有分子亚型病理信息的对象，排除转移性乳腺癌及有内分泌相关疾病、精神障碍的患者，最终共纳入437例。对照组为同期来源于四川省人民医院和成都市双流妇幼保健院的健康体检人群，经超声和钼靶检查后排除患有其它恶性肿瘤及精神障碍者，最终纳入469例。所有研究对象均签署了知情同意书，且本研究方案由四川大学伦理委员会批准(批号：scuhx4 h2013003)。

    1.2   资料收集

    本次研究采用统一编制的结构化调查问卷，由经过统一培训的调查员进行信息收集。问卷内容包括一般人口学特征、生活习惯、女性生殖生育史、慢性疾病史、肿瘤家族史，调查现场测量研究对象的体质量、身高、腰围、臀围并计算出体质指数(body mass index, BMI)和腰臀比(waist-to-hip ratio, WHR)。从医院电子病历收集病例组的临床病理信息，包括雌激素受体(estrogen receptor, ER)、孕激素受体(progestogen receptor, PR)、人表皮生长因子受体-2(HER-2)和Ki-67的结果。

    1.3   实验室检测

    病例组和对照组分别于手术前2~3 d和现场调查当天采用EDTA抗凝管收集空腹外周静脉血5 mL，收集后数小时内以1 000×g离心15 min分离血浆，并在-80 ℃下冷冻储存。血浆脂联素浓度的测定采用酶联免疫吸附试验(ELASA)，相关试剂盒购自武汉伊莱瑞特生物科技股份有限公司(产品货号：E-EL-H0004c)，测定严格遵循试剂盒的说明。

    1.4   乳腺癌分子亚型定义

    参考《中国抗癌协会乳腺癌诊治指南与规范(2017年版)》[8]，根据ER、PR、HER-2和Ki-67状态将乳腺癌划分为4类分子亚型，分别是Luminal A型、Luminal B型、HER-2过表达型和基底型, 其中Luminal A型和Luminal B型在病原学方面具有相似性[9]，在本次研究中合并为Luminal型。

    1.5   统计学方法

    统计分析时将研究对象按绝经状态分层。定量变量若服从或近似服从正态分布，则以x±s表示，用方差分析进行均数间比较，否则以中位数(P25，P75)表示，使用Kruskal-Wallis H秩和检验进行样本间比较。定性变量以例数(%)表示，组间比较采用χ2检验。按对照组血浆脂联素水平的四分位数将研究对象分为4类，采用无序多分类logistic回归分析血浆脂联素水平与不同分子亚型乳腺癌发生风险的关系，调整混杂因素后计算OR值及其95%置信区间。采用趋势卡方检验分析不同分子亚型组与血浆脂联素水平间是否具有线性趋势，并计算P趋势值。α双侧=0.05。

    2.   结果

    2.1   基本信息

    对照组共469例，病例组共437例，其中Luminal型310例、HER-2过表达型83例、基底型44例，WHR、文化程度、主动吸烟、饮绿茶、活产次数、良性乳腺疾病史、肿瘤家族史在对照组和不同分子亚型病例组间分布差异有统计学意义(P < 0.05)，详见表 1。按照绝经状态分层后，绝经前对照组231例，病例组Luminal型171例，HER-2过表达型40例，基底型20例，WHR、文化程度、绿茶、活产次数在不同亚组间分布有统计学差异(P < 0.05)；绝经后对照组238例，病例组Luminal型139例，HER-2过表达型43例，基底型24例，WHR、文化程度、主动吸烟、饮酒、良性乳腺疾病史、肿瘤家族史在不同亚组间分布差异有统计学意义(P < 0.05)。

    表  1  不同分子亚型乳腺癌病例组与对照组的基线特征比较
    Table  1.  Comparison of baseline characteristics between breast cancer cases with different subtypes and controls
    Characteristic Controls
    (n=469)    		 Luminal
    (n=310)    		 HER-2-enriched
    (n=83)    		 Basal-like
    (n=44)    		 P
    Age/yr. 50.39±9.26 50.36±9.45 50.22±8.29 50.93±11.98 0.981
    BMI/(kg/m2) 23.50±3.03 23.29±3.02 23.17±2.81 23.00±2.74 0.548
    WHR* 0.84 (0.80, 0.89) 0.81 (0.75, 0.86) 0.80 (0.75, 0.86) 0.82 (0.74, 0.90) < 0.001
    Menarche age*/yr. 14 (13, 15) 14 (13, 15) 14 (13, 16) 14 (13, 14.75) 0.652
    Age at first live birth*/yr. 24 (22, 26) 24 (23, 26) 24 (22, 26) 23 (21.75, 25.25) 0.223
    Education level/case (%) < 0.001
      ＜High school 338 (72.1) 260 (83.9) 75 (90.4) 37 (84.1)
      ≤High school 131 (27.9) 50 (16.1) 8 (9.6) 7 (15.9)
    Active smoking/case (%) 0.014
      Yes 3 (0.6) 9 (2.9) 4 (4.8) 2 (4.5)
      No 466 (99.4) 301 (97.1) 79 (95.2) 42 (95.5)
    Alcohol drinking/case (%) 0.591
      Yes 14 (3.0) 12 (3.9) 3 (3.6) 3 (6.8)
      No 455 (97.0) 298 (96.1) 80 (96.4) 41 (93.2)
    Green tea drinking/case (%) 0.014
      Yes 82 (17.5) 39 (12.6) 4 (4.8) 6 (13.6)
      No 387 (82.5) 271 (87.4) 79 (95.2) 38 (86.4)
    Number of abortion/case (%) 0.925
      0-1 278 (59.3) 181 (58.6) 48 (57.8) 28 (63.6)
      ≥2 191 (40.7) 128 (41.4) 35 (42.2) 16 (36.4)
    Number of live birth/case (%) < 0.001
      0-1 359 (76.5) 193 (62.3) 50 (60.2) 27 (61.4)
      ≥2 110 (23.5) 117 (37.7) 33 (39.8) 17 (38.6)
    History of benign breast disease/case (%) 0.009
      Yes 61 (15.6) 69 (26.3) 17 (22.7) 7 (18.9)
      No 329 (84.4) 193 (73.7) 58 (77.3) 30 (81.1)
    Family history of breast cancer/case (%) 0.021
      Yes 80 (17.1) 78 (25.2) 19 (22.9) 13 (29.5)
      No 389 (82.9) 232 (74.8) 64 (77.1) 31 (70.5)
    BMI: Body mass index; WHR: Waist-to-hip ratio；* P50 (P25, P75)
    下载: 导出CSV 
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    2.2   不同分子亚型病例组与对照组血浆脂联素分布及差异

    对照组血浆脂联素水平中位数(P25, P75)为14.85(9.69, 21.35) μg/mL；病例组Luminal型、HER-2过表达型和基底型血浆脂联素水平中位数(P25, P75)为11.74(8.15, 16.14) μg/mL、12.02(8.43, 16.96) μg/mL和12.67(8.25, 17.27) μg/mL。未按绝经状态分层时，病例组各分子亚型与对照组相比血浆脂联素分布差异均有统计学意义(P < 0.05)。按照绝经状态分层后，绝经前Luminal型血浆脂联素分布与对照组相比差异有统计学意义(P < 0.05)，绝经后Luminal型、HER-2过表达型血浆脂联素分布与对照组相比差异有统计学意义(P < 0.05)，详见表 2。

    表  2  不同分子亚型乳腺癌和对照组的血浆脂联素水平差异〔中位数(P25，P75)〕
    Table  2.  Differences in plasma adiponectin levels between breast cancer cases with different subtypes and controls (P50(P25, P75))
    Group Adiponectina Premenopausal-adiponectinb Postmenopausal-adiponectinb
    n ρ/(μg/mL) n ρ/(μg/mL) n ρ/(μg/mL)
    Controls 469 14.85 (9.69, 21.35) 231 13.37 (9.11, 17.08) 238 17.77 (10.31, 24.95)
    Luminal 310 11.74 (8.15, 16.14)* 171 11.06 (7.67, 15.06)* 139 12.54 (8.97, 17.78)*
    HER-2-enriched 83 12.02 (8.43, 16.96)* 40 10.85 (7.31, 18.07) 43 12.24 (9.41, 16.96)*
    Basal-like 44 12.67 (8.25, 17.27)* 20 11.10 (6.80, 14.15) 24 14.50 (9.82, 18.25)
    a: Adiponectin level obeyed the normal distribution and homogeneity of variance after logarithmic transformation. The result of the analysis of variance between the different molecular subtypes and the control group was statistically significant. Pairwise comparisons were conducted by the Dunnet-t test; b: After stratified by menopausal status, adiponectin level were no longer normally distributed. The result of Kruskal-Wallis H rank sum test between the different molecular subtypes and the control group was statistically significant. Pairwise comparisons were conducted by the Bonferroni method to adjust the alpha level; *Statistically different from the control group
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    2.3   不同水平血浆脂联素与不同分子亚型乳腺癌发生风险

    模型纳入变量说明见表 3，无序多分类logistic回归显示，在调整了混杂因素之后，未按绝经状态分层时，与对照组相比，3种分子亚型血浆脂联素水平越高，乳腺癌发生风险越低。按照绝经状态分层后，与对照组相比，血浆脂联素水平越高，绝经前Luminal型乳腺癌(OR绝经前Luminal=0.50，95%CI：0.27~0.92；χ趋势2=10.837，P趋势=0.001)、绝经后Luminal型和HER-2过表达型(OR绝经后Luminal=0.06，95%CI：0.02~0.23；χ趋势2=22.999，P趋势 < 0.001；OR绝经后HER-2+=0.06，95%CI：0.01~0.62；χ趋势2=10.722，P趋势=0.001)发生风险越低，且绝经后血浆脂联素对Luminal型的保护效应较绝经前更大。未发现血浆脂联素与绝经前后基底型乳腺癌发生风险相关。具体结果见表 4~表 6。

    表  3  变量赋值
    Table  3.  Variable assignment
    Variable Coding
    Age Continuous variable
    BMI Continuous variable
    WHR Continuous variable
    Menarche age Continuous variable
    Age at first live birth Continuous variable
    Educational level Below high school=1，high school or above=2
    Active smoking No=1，yes=2
    Alcohol drinking No=1，yes=2
    Green tea No=1，yes=2
    Number of abortion 1=1，≥2=2
    Number of live birth 1=1，≥2=2
    History of benign breast disease No=1，yes=2
    Family history of breast cancer No=1，yes=2
    Outcome Controls=0(ref)，Luminal=1，HER2-enriched=2，basal-like=3
    Plasma adiponectin Highest level=1，second level=2，third level=3，lowest level=4 (ref)
    ref: Reference
    下载: 导出CSV 
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    表  4  血浆脂联素与不同分子亚型乳腺癌发生风险的无序多分类logistic回归分析
    Table  4.  Multinomial logistic regression analysis of the relationship between plasma adiponectin level and risk of breast cancer by molecular subtypes
    Adiponectin/ (μg/mL) Controls (n=469)/ case (%) Luminal (n=310) HER2-enriched (n=83) Basal-like (n=44)
    Case (%) OR (95%CI)* Case (%) OR (95%CI)* Case (%) OR (95%CI)*
    ≤9.69 117 (24.9) 110 (35.5) 1.00 (ref) 28 (33.7) 1.00 (ref) 13 (29.5) 1.00 (ref)
    9.70-14.85 118 (25.2) 105 (33.9) 0.91 (0.59-1.40) 25 (30.1) 0.79 (0.41-1.53) 16 (36.4) 1.11 (0.47-2.62)
    14.86-21.35 117 (24.9) 70 (22.6) 0.71 (0.44-1.13) 20 (24.1) 0.79 (0.39-1.60) 12 (27.3) 1.05 (0.42-2.61)
    > 21.35 117 (24.9) 25 (8.1) 0.19 (0.11-0.35)△ 10 (12.0) 0.37 (0.16-0.84)△ 3 (6.8) 0.25 (0.07-0.94)△
    * Adjusted for WHR, educational level, active smoking, green tea, number of live birth, history of benign breast disease and family history of breast cancer. ref: Reference, △P < 0.05
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    表  5  绝经前血浆脂联素与不同分子分型乳腺癌发生风险的无序多分类logistic回归分析
    Table  5.  Multinomial logistic regression analysis of the relationship between plasma adiponectin level and risk of pre-menopausal breast cancer by molecular subtypes
    Adiponectin/ (μg/mL) Controls (n=231)/ case (%) Luminal (n=171) HER2-enriched (n=40) Basal-like (n=20)
    Case (%) OR (95%CI)* Case (%) OR (95%CI)* Case (%) OR (95%CI)*
    ≤9.11 58 (25.1) 62 (36.3) 1.00 (ref) 15 (37.5) 1.00 (ref) 8 (40.0) 1.00 (ref)
    9.11-13.37 58 (25.1) 54 (31.6) 0.83 (0.48-1.44) 8 (20.0) 0.49 (0.19-1.27) 4 (20.0) 0.45 (0.13-1.60)
    13.37-17.08 58 (25.1) 27 (15.8) 0.41 (0.22-0.76)△ 7 (17.5) 0.43 (0.16-1.16) 6 (30.0) 0.68 (0.22-2.12)
    > 17.08 57 (24.7) 28 (16.4) 0.50 (0.27-0.92)△ 10 (25.0) 0.71 (0.29-1.74) 2 (10.0) 0.26 (0.05-1.30)
    * Adjusted for WHR, educational level, green tea and number of live birth. ref: Reference. △P < 0.05
    下载: 导出CSV 
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    表  6  绝经后血浆脂联素与不同分子分型乳腺癌发生风险的无序多分类logistic回归分析
    Table  6.  Multinomial logistic regression analysis of the relationship between plasma adiponectin level and risk of post-menopausal breast cancer by molecular subtypes
    Adiponectin/ (μg/mL) Controls (n=238)/ case (%) Luminal (n=139) HER2-enriched (n=43) Basal-like (n=24)
    Case (%) OR (95%CI)* Case (%) OR (95%CI)* Case (%) OR (95%CI)*
    ≤10.31 59 (24.8) 46 (33.1) 1.00 (ref) 12 (27.9) 1.00 (ref) 9 (37.5) 1.00 (ref)
    10.31-17.77 61 (25.6) 58 (41.7) 1.33 (0.71-2.49) 24 (55.8) 2.17 (0.89-5.30) 9 (37.5) 1.21 (0.39-3.77)
    17.77-24.95 59 (24.8) 30 (21.6) 0.52 (0.26-1.07) 6 (14.0) 0.47 (0.14-1.55) 4 (16.7) 0.31 (0.06-1.61)
    > 24.95 59 (24.8) 5 (3.6) 0.06 (0.02-0.23)△ 1 (2.3) 0.06 (0.01-0.62)△ 2 (8.3) 0.20 (0.03-1.32)
    * Adjusted for WHR, educational level, active smoking, alcohol drinking, history of benign breast disease and family history of breast cancer. ref: Reference. △P < 0.05
    下载: 导出CSV 
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    3.   讨论

    脂联素主要由白色脂肪细胞分泌，通过脂联素受体介导，可以诱导磷酸腺苷依赖的蛋白激酶(AMPK)活化从而起到抗细胞增殖的作用，或是激活caspase途径促进肿瘤细胞的凋亡[4]。目前，流行病学研究证据倾向于血浆脂联素是乳腺癌发病的保护因素。一项纳入15个观察性研究的Meta分析显示，高循环脂联素水平相对于低水平能够降低乳腺癌发生风险(合并相对危险度=0.34, 95%CI: 0.13~0.50)，且存在剂量反应关系，血浆脂联素水平每增加3 mg/mL，乳腺癌发生风险降低5%(95%CI: 1%~9%)[6]；GROSS等[7]通过一项前瞻性研究提示低水平血浆脂联素浓度能够增加绝经后乳腺癌发生风险(OR=1.63, 95%CI: 1.02~2.60)。但既往研究均未考虑血浆脂联素对不同分子亚型乳腺癌的效应是否存在差别。

    本次研究发现，高水平血浆脂联素对绝经前后Luminal型乳腺癌均具有保护效应，且对绝经后的保护效应大于绝经前。Luminal型指ER和(或)PR阳性的乳腺癌亚型，构成中国女性乳腺癌的68.5%[10]。一些体外和体内基础研究显示，脂联素对乳腺癌的作用依赖于细胞表型，在ER阳性细胞中低脂联素水平能够促进肿瘤细胞增殖，在ER阴性细胞中则作用相反[11]。脂联素的作用是否和绝经状态有关目前还存在争议，一些研究认为脂联素对绝经前后乳腺癌发生的影响一致，而LIU等[12]研究提示高水平血浆脂联素对绝经后乳腺癌发生的保护效应更大，与本次研究结论一致。这种差异可能是由于血浆脂联素与雌激素的表达相关，有研究报道血浆脂联素浓度与绝经后女性的血清雌二醇浓度呈负相关，与绝经前妇女则无相关[13]。

    HER-2过表达型指ER和PR阴性、HER-2阳性的乳腺癌，本研究发现其发生风险与血浆脂联素水平呈负相关，但仅体现在绝经后女性。WOO等[14]研究发现在ER阴性的细胞中，血浆脂联素同样能起到抑制细胞增殖和促进细胞凋亡的作用，且高水平血浆脂联素在ER/PR阴性乳腺癌中更能导致良好的预后。原癌基因HER-2的表达与乳腺癌预后不良有关，且HER-2表达与ER/PR表达存在反向关系[15]，但缺乏血浆脂联素与HER-2表达的相关机制研究。本研究提示高水平血浆脂联素仅对绝经后女性发生HER-2过表达型乳腺癌具有保护效应，可能与绝经前后激素表达存在差异、发病危险因素不同有关，具体机制有待研究。

    基底型乳腺癌指ER、PR和HER-2均为阴性表达，相比于其它亚型其侵袭性最高且预后最差。SULTANA等[16]研究发现血浆脂联素与基底型乳腺癌严重程度呈负相关，JEONG等[17]研究提示具有高侵袭性的乳腺癌更容易表达脂联素。肥胖/超重与乳腺癌发生风险的相关研究中提示高BMI会增加基底型乳腺癌的发生风险[18]，而血浆脂联素表达与BMI则存在负相关[13]。以上研究均可间接提示血浆脂联素水平与基底型乳腺癌发生风险存在相关性。本次研究发现高脂联素水平是基底型乳腺癌发生风险的保护因素，但亚组分析则显示绝经前后都不存在这种关联。这可能是由于按照绝经状态分层后，基底型乳腺癌样本数太少，导致检验效能不足。

    本次研究探讨了血浆脂联素对不同分子亚型乳腺癌发生风险的影响，考虑了乳腺癌亚型间存在异质性的问题，这种研究角度较为新颖。但该研究仍存在以下局限性：第一，脂联素存在多种构型，且不同构型对乳腺癌的作用可能存在差别[3]，但本次研究只检测了总脂联素水平；第二，本次研究总体样本量大，但按绝经状态分层后部分分子亚型组样本量较小，可能导致检验效能不足。

    本研究结果提示高脂联素水平能够降低绝经前后Luminal型和绝经后HER-2过表达型乳腺癌的发生风险，且Luminal型为我国女性最常见的乳腺癌亚型[10]，故血浆脂联素能够成为较好的乳腺癌发生风险指示指标。未来仍需要进一步的研究，通过多中心大样本人群验证，寻找稳定的指示乳腺癌发生风险的生物标志物，进而为乳腺癌的精准预防提供证据。

  • 表  1   不同分子亚型乳腺癌病例组与对照组的基线特征比较

    Table  1   Comparison of baseline characteristics between breast cancer cases with different subtypes and controls

    Characteristic Controls
    (n=469)    		 Luminal
    (n=310)    		 HER-2-enriched
    (n=83)    		 Basal-like
    (n=44)    		 P
    Age/yr. 50.39±9.26 50.36±9.45 50.22±8.29 50.93±11.98 0.981
    BMI/(kg/m2) 23.50±3.03 23.29±3.02 23.17±2.81 23.00±2.74 0.548
    WHR* 0.84 (0.80, 0.89) 0.81 (0.75, 0.86) 0.80 (0.75, 0.86) 0.82 (0.74, 0.90) < 0.001
    Menarche age*/yr. 14 (13, 15) 14 (13, 15) 14 (13, 16) 14 (13, 14.75) 0.652
    Age at first live birth*/yr. 24 (22, 26) 24 (23, 26) 24 (22, 26) 23 (21.75, 25.25) 0.223
    Education level/case (%) < 0.001
      ＜High school 338 (72.1) 260 (83.9) 75 (90.4) 37 (84.1)
      ≤High school 131 (27.9) 50 (16.1) 8 (9.6) 7 (15.9)
    Active smoking/case (%) 0.014
      Yes 3 (0.6) 9 (2.9) 4 (4.8) 2 (4.5)
      No 466 (99.4) 301 (97.1) 79 (95.2) 42 (95.5)
    Alcohol drinking/case (%) 0.591
      Yes 14 (3.0) 12 (3.9) 3 (3.6) 3 (6.8)
      No 455 (97.0) 298 (96.1) 80 (96.4) 41 (93.2)
    Green tea drinking/case (%) 0.014
      Yes 82 (17.5) 39 (12.6) 4 (4.8) 6 (13.6)
      No 387 (82.5) 271 (87.4) 79 (95.2) 38 (86.4)
    Number of abortion/case (%) 0.925
      0-1 278 (59.3) 181 (58.6) 48 (57.8) 28 (63.6)
      ≥2 191 (40.7) 128 (41.4) 35 (42.2) 16 (36.4)
    Number of live birth/case (%) < 0.001
      0-1 359 (76.5) 193 (62.3) 50 (60.2) 27 (61.4)
      ≥2 110 (23.5) 117 (37.7) 33 (39.8) 17 (38.6)
    History of benign breast disease/case (%) 0.009
      Yes 61 (15.6) 69 (26.3) 17 (22.7) 7 (18.9)
      No 329 (84.4) 193 (73.7) 58 (77.3) 30 (81.1)
    Family history of breast cancer/case (%) 0.021
      Yes 80 (17.1) 78 (25.2) 19 (22.9) 13 (29.5)
      No 389 (82.9) 232 (74.8) 64 (77.1) 31 (70.5)
    BMI: Body mass index; WHR: Waist-to-hip ratio；* P50 (P25, P75)
    下载: 导出CSV

    表  2   不同分子亚型乳腺癌和对照组的血浆脂联素水平差异〔中位数(P25，P75)〕

    Table  2   Differences in plasma adiponectin levels between breast cancer cases with different subtypes and controls (P50(P25, P75))

    Group Adiponectina Premenopausal-adiponectinb Postmenopausal-adiponectinb
    n ρ/(μg/mL) n ρ/(μg/mL) n ρ/(μg/mL)
    Controls 469 14.85 (9.69, 21.35) 231 13.37 (9.11, 17.08) 238 17.77 (10.31, 24.95)
    Luminal 310 11.74 (8.15, 16.14)* 171 11.06 (7.67, 15.06)* 139 12.54 (8.97, 17.78)*
    HER-2-enriched 83 12.02 (8.43, 16.96)* 40 10.85 (7.31, 18.07) 43 12.24 (9.41, 16.96)*
    Basal-like 44 12.67 (8.25, 17.27)* 20 11.10 (6.80, 14.15) 24 14.50 (9.82, 18.25)
    a: Adiponectin level obeyed the normal distribution and homogeneity of variance after logarithmic transformation. The result of the analysis of variance between the different molecular subtypes and the control group was statistically significant. Pairwise comparisons were conducted by the Dunnet-t test; b: After stratified by menopausal status, adiponectin level were no longer normally distributed. The result of Kruskal-Wallis H rank sum test between the different molecular subtypes and the control group was statistically significant. Pairwise comparisons were conducted by the Bonferroni method to adjust the alpha level; *Statistically different from the control group
    下载: 导出CSV

    表  3   变量赋值

    Table  3   Variable assignment

    Variable Coding
    Age Continuous variable
    BMI Continuous variable
    WHR Continuous variable
    Menarche age Continuous variable
    Age at first live birth Continuous variable
    Educational level Below high school=1，high school or above=2
    Active smoking No=1，yes=2
    Alcohol drinking No=1，yes=2
    Green tea No=1，yes=2
    Number of abortion 1=1，≥2=2
    Number of live birth 1=1，≥2=2
    History of benign breast disease No=1，yes=2
    Family history of breast cancer No=1，yes=2
    Outcome Controls=0(ref)，Luminal=1，HER2-enriched=2，basal-like=3
    Plasma adiponectin Highest level=1，second level=2，third level=3，lowest level=4 (ref)
    ref: Reference
    下载: 导出CSV

    表  4   血浆脂联素与不同分子亚型乳腺癌发生风险的无序多分类logistic回归分析

    Table  4   Multinomial logistic regression analysis of the relationship between plasma adiponectin level and risk of breast cancer by molecular subtypes

    Adiponectin/ (μg/mL) Controls (n=469)/ case (%) Luminal (n=310) HER2-enriched (n=83) Basal-like (n=44)
    Case (%) OR (95%CI)* Case (%) OR (95%CI)* Case (%) OR (95%CI)*
    ≤9.69 117 (24.9) 110 (35.5) 1.00 (ref) 28 (33.7) 1.00 (ref) 13 (29.5) 1.00 (ref)
    9.70-14.85 118 (25.2) 105 (33.9) 0.91 (0.59-1.40) 25 (30.1) 0.79 (0.41-1.53) 16 (36.4) 1.11 (0.47-2.62)
    14.86-21.35 117 (24.9) 70 (22.6) 0.71 (0.44-1.13) 20 (24.1) 0.79 (0.39-1.60) 12 (27.3) 1.05 (0.42-2.61)
    > 21.35 117 (24.9) 25 (8.1) 0.19 (0.11-0.35)△ 10 (12.0) 0.37 (0.16-0.84)△ 3 (6.8) 0.25 (0.07-0.94)△
    * Adjusted for WHR, educational level, active smoking, green tea, number of live birth, history of benign breast disease and family history of breast cancer. ref: Reference, △P < 0.05
    下载: 导出CSV

    表  5   绝经前血浆脂联素与不同分子分型乳腺癌发生风险的无序多分类logistic回归分析

    Table  5   Multinomial logistic regression analysis of the relationship between plasma adiponectin level and risk of pre-menopausal breast cancer by molecular subtypes

    Adiponectin/ (μg/mL) Controls (n=231)/ case (%) Luminal (n=171) HER2-enriched (n=40) Basal-like (n=20)
    Case (%) OR (95%CI)* Case (%) OR (95%CI)* Case (%) OR (95%CI)*
    ≤9.11 58 (25.1) 62 (36.3) 1.00 (ref) 15 (37.5) 1.00 (ref) 8 (40.0) 1.00 (ref)
    9.11-13.37 58 (25.1) 54 (31.6) 0.83 (0.48-1.44) 8 (20.0) 0.49 (0.19-1.27) 4 (20.0) 0.45 (0.13-1.60)
    13.37-17.08 58 (25.1) 27 (15.8) 0.41 (0.22-0.76)△ 7 (17.5) 0.43 (0.16-1.16) 6 (30.0) 0.68 (0.22-2.12)
    > 17.08 57 (24.7) 28 (16.4) 0.50 (0.27-0.92)△ 10 (25.0) 0.71 (0.29-1.74) 2 (10.0) 0.26 (0.05-1.30)
    * Adjusted for WHR, educational level, green tea and number of live birth. ref: Reference. △P < 0.05
    下载: 导出CSV

    表  6   绝经后血浆脂联素与不同分子分型乳腺癌发生风险的无序多分类logistic回归分析

    Table  6   Multinomial logistic regression analysis of the relationship between plasma adiponectin level and risk of post-menopausal breast cancer by molecular subtypes

    Adiponectin/ (μg/mL) Controls (n=238)/ case (%) Luminal (n=139) HER2-enriched (n=43) Basal-like (n=24)
    Case (%) OR (95%CI)* Case (%) OR (95%CI)* Case (%) OR (95%CI)*
    ≤10.31 59 (24.8) 46 (33.1) 1.00 (ref) 12 (27.9) 1.00 (ref) 9 (37.5) 1.00 (ref)
    10.31-17.77 61 (25.6) 58 (41.7) 1.33 (0.71-2.49) 24 (55.8) 2.17 (0.89-5.30) 9 (37.5) 1.21 (0.39-3.77)
    17.77-24.95 59 (24.8) 30 (21.6) 0.52 (0.26-1.07) 6 (14.0) 0.47 (0.14-1.55) 4 (16.7) 0.31 (0.06-1.61)
    > 24.95 59 (24.8) 5 (3.6) 0.06 (0.02-0.23)△ 1 (2.3) 0.06 (0.01-0.62)△ 2 (8.3) 0.20 (0.03-1.32)
    * Adjusted for WHR, educational level, active smoking, alcohol drinking, history of benign breast disease and family history of breast cancer. ref: Reference. △P < 0.05
    下载: 导出CSV
    • 参考文献(18)
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    CHEN W, ZHENG R, BAADE P D, et al. Cancer statistics in China, 2015. CA-Cancr J Clin, 2016, 66(2):115-132. DOI: 10.3322/caac.21338
    [2] 曹明丽.基于分子分型的乳腺癌流行病学新认识.中国肿瘤临床, 2017, 44(9):449-451. DOI: 10.3969/j.issn.1000-8179.2017.09.180
    [3] 尹庚申, 郭明明, 余之刚.脂联素及其受体在肥胖相关的乳腺癌中的作用.中华乳腺病杂志(电子版), 2018, 12(4):246-249. DOI: 10.3877/cma.j.issn.1674-0807.2018.04.011
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    PANNO M L, NAIMO G D, SPINA E, et al. Different molecular signaling sustaining adiponectin action in breast cancer. Curr Opin Pharmacol, 2016, 31:1-7. DOI: 10.1016/j.coph.2016.08.001
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    AHMED S D, KHANAM A, SULTAN N, et al. Serum adiponectin level association with breast cancer risk: evidence from a case-control study. Asian Pac J Cancer Prev, 2015, 16(12):4945-4948. DOI: 10.7314/APJCP.2015.16.12.4945
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    MACIS D, GUERRIERIGONZAGA A, GANDINI S. Circulating adiponectin and breast cancer risk: a systematic review and meta-analysis. Int J Epidemiol, 2014, 43(4):1226-1236. DOI: 10.1093/ije/dyu088
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出版历程
  • 收稿日期:  2019-02-20
  • 修回日期:  2019-06-14
  • 网络出版日期:  2021-03-16
  • 发布日期:  2019-09-19

目录

摘要
HTML全文

  • 1.   对象与方法

  • 1.1   研究对象

  • 1.2   资料收集

  • 1.3   实验室检测

  • 1.4   乳腺癌分子亚型定义

  • 1.5   统计学方法

  • 2.   结果

  • 2.1   基本信息

  • 2.2   不同分子亚型病例组与对照组血浆脂联素分布及差异

  • 2.3   不同水平血浆脂联素与不同分子亚型乳腺癌发生风险

  • 3.   讨论

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