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中华乳腺病杂志(电子版)

中华乳腺病杂志(电子版) ›› 2014, Vol. 08 ›› Issue (03) : 170 -175. doi: 10.3877/cma. j. issn.1674-0807.2014.03.004

论著

散发性乳腺癌中DJ-1 蛋白高表达与不良预后
朱玄1,2, 辛世杰1,2,†()   
  1. 1.114001 辽宁鞍山,中国医科大学附属第一医院鞍山医院普通外科
    2.110001 沈阳,中国医科大学附属第一医院普通外科
  • 收稿日期:2014-02-07 出版日期:2014-06-01
  • 通信作者: 辛世杰
  • 基金资助:
    国家自然科学基金资助项目(81170295)

High expression of DJ-1 protein related to poor prognosis in sporadic breast cancer

Xuan Zhu1, Shijie Xin1,†()   

  1. 1.Department of General Surgery, Anshan Hospital, First Affiliated Hospital of China Medical University, Anshan 114001, China
  • Received:2014-02-07 Published:2014-06-01
  • Corresponding author: Shijie Xin
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朱玄, 辛世杰. 散发性乳腺癌中DJ-1 蛋白高表达与不良预后[J]. 中华乳腺病杂志(电子版), 2014, 08(03): 170-175.

Xuan Zhu, Shijie Xin. High expression of DJ-1 protein related to poor prognosis in sporadic breast cancer[J]. Chinese Journal of Breast Disease(Electronic Edition), 2014, 08(03): 170-175.

目的

探讨DJ-1 蛋白表达水平在散发性乳腺癌发生、发展及预后中的临床意义。

方法

采用免疫组织化学法检测了包含199 例散发性乳腺癌组织与160 例乳腺良性增生组织的组织微阵列芯片中DJ-1 蛋白的表达情况,同时应用酶联免疫吸附试验检测48 例散发性乳腺癌及35 例乳腺良性增生患者血清中DJ-1 蛋白的水平,并分析组织中DJ-1 蛋白表达水平与乳腺癌患者临床病理指标及生存资料的相关性。 统计分析采用Pearson χ2 检验和独立样本t 检验;生存分析采用log-rank 检验绘制Kaplan-Meier曲线,Cox 回归用于进行多变量分析。

结果

DJ-1 蛋白在乳腺良性增生组织及乳腺癌组织中阳性表达率分别为33.8%(54/160)、48.7%(97/199),在乳腺良性增生及乳腺癌患者血清中DJ-1 蛋白平均水平分别为(25.86±7.28)ng/ml 和(31.31±8.39)ng/ml,与乳腺良性增生相比,乳腺癌组织(χ2 =8.182, P=0.004)及血清(t=3.161, P=0.002)中DJ-1 蛋白的表达水平均显著增加;淋巴结转移阳性的乳腺癌组织与阴性组织相比,DJ-1 表达水平显著增加(χ2=5.372, P=0.020);随着组织学分级的增加,浸润性导管癌中DJ-1 表达水平显著增高(χ2 =5.244, P=0.022);DJ-1 阳性表达与患者生存期缩短显著相关(OS: χ2=5.427,P=0.020; χ2=4.606,DFS: P=0.032)。 单变量Cox 回归分析发现,DJ-1 表达水平作为危险因素与患者的OS 及DFS 显著相关(OS: P=0.023; DFS: P=0.036),但多变量Cox 回归分析发现,DJ-1 表达水平并非影响患者预后的独立风险因素(OS: P=0.561; DFS: P=0.342)。

结论

在散发性乳腺癌中,DJ-1 蛋白表达水平显著增高,其高表达与乳腺癌的侵袭转移、病程进展及不良预后相关。

关键词: DJ-1, 乳腺肿瘤, 免疫组织化学, 生存分析

Objective

To explore the clinical significance of DJ-1 protein expression in the development and prognosis of sporadic breast cancer.

Methods

DJ-1 protein expression was detected by immunohistochemistry in tissue microarray chips containing 199 cases of sporadic breast cancer tissues and 160 cases of breast benign hyperplasia tissues. Serous DJ-1 protein levels in 48 sporadic breast cancer cases and 35 breast benign hyperplasia cases were detected by enzyme linked immunosorbent assay. And the correlation was analyzed between DJ-1 protein expression and clinicopathologic parameters and survival data. The data were processed by Pearson χ2 test and independent sample t-test;the log-rank test and Kaplan-Meier curve were used for survival analysis, Cox regression for multivariate analysis.

Results

The positive expression rates of DJ-1 protein were 33.8% (54/160) in breast benign hyperplasia and 48.7% (97/199) in breast cancer tissue respectively(χ2 = 8.182, P = 0.004). Serous DJ-1 levels were (25.86±7.28) ng/ml in breast benign hyperplasia and (31.31±8.39) ng/ml in breast cancer tissue respectively(t=3.161,P=0.002). DJ-1 protein level was higher significantly in breast cancer patients with lymph nodes positive than in patients with lymph nodes negative (χ2=5.372, P=0.020). DJ-1 protein level was increased significantly with the increase of histological grade (χ2 =5.244, P=0.022). DJ-1 positive expression was associated significantly with poor prognosis of breast cancer patients (OS: χ2=5.427,P=0.020; DFS: χ2=4.606,P=0.032). Univariate Cox regression analysis showed that DJ-1 expression was a risk factor associated significantly with OS and DFS of the patients (OS: P = 0.023; DFS: P = 0.036); but multivariate Cox regression analysis showed that DJ-1 expression was not an independent risk factor in the prognosis of breast cancer patients (OS: P=0.561; DFS: P=0.342).

Conclusion

DJ-1 protein expression is increased significantly in sporadic breast cancer, which is associated significantly with the metastasis, progression and poor prognosis of breast cancer.

Key words: DJ-1, Breast neoplasms, Immunohistochemistry, Survival analysis
表1 乳腺癌患者各病理参数量化赋值表
病理参数 量化赋值
年龄 ≤50岁=1,＞50岁=2
月经状态 未绝经=1,已绝经=2
肿瘤类型 导管癌=1,小叶癌=2
肿瘤直径 ≤5.0 cm=1,＞5.0 cm=2
TNM分期 Ⅰ~Ⅱ=1,Ⅲ~Ⅳ=2
淋巴结转移 否=0,是=1
组织学分级 Ⅰ~Ⅱ=1,Ⅲ=2
DJ-1表达 阴性=1,阳性=2
表2 乳腺癌病理参数与DJ-1 蛋白表达的相关性
病理参数 总例数 阳性例数 阳性率(%) χ 2值 P值
年龄(岁) 0.245 0.621
≤50 100 47 47.0
＞50 99 50 50.5
月经状态a 0.005 0.943
未绝经 91 44 48.4
已绝经 92 44 47.8
肿瘤直径(cm)b 0.188 0.664
≤5.0 149 73 49.0
＞5.0 30 16 53.3
淋巴结转移c 5.372 0.020
否 78 30 38.5
是 102 57 55.9
肿瘤类型 0.680 0.409
导管癌 179 89 49.7
小叶癌 20 8 40.0
TNM分期d 0.886 0.347
Ⅰ~Ⅱ 118 56 47.5
Ⅲ~Ⅳ 62 34 54.8
组织学分级e 5.244 0.022
Ⅰ~Ⅱ 93 40 43.0
Ⅲ 35 23 65.7
图1 DJ-1 蛋白在乳腺良性增生及乳腺癌组织中的阴性表达和阳性表达(SP ×400;放大图: ×1000) a: 乳腺良性增生组织DJ-1 蛋白阴性表达;b: 乳腺癌组织DJ-1 蛋白阴性表达;c: 乳腺良性增生组织DJ-1 蛋白阳性表达;d: 乳腺癌组织DJ-1 蛋白阳性表达;箭头表示放大图的位置
图2 DJ-1 蛋白表达对乳腺癌患者生存期的影响 a: DJ-1 表达可显著缩短乳腺癌患者OS,χ2=5.427,P=0.020;b: DJ-1 表达可显著缩短乳腺癌患者DFS,χ2=4.606,P=0.032;log-rank 检验法
表3 单变量分析临床病理参数与乳腺癌患者总生存及无瘤生存的相关性
变量 例数 总生存 无瘤生存
RR值 95%CI P值 RR值 95%CI P值
年龄(＞50岁/≤50岁) 145 1.320 0.732~2.381 0.356 1.492 0.862~2.581 0.153
绝经状态(绝经后/绝经前) 133 1.369 0.746~2.509 0.311 1.231 0.704~2.152 0.466
肿瘤类型(小叶癌/导管癌) 145 1.628 0.572~4.636 0.361 1.114 0.397~3.122 0.838
肿瘤直径(＞5.0 cm/≤5.0 cm) 137 3.155 1.744~5.709 0.000 2.461 1.403~4.318 0.002
淋巴结转移(是/否) 138 8.482 3.034~23.710 0.000 6.806 2.907~15.937 0.000
TNM分期(Ⅲ~Ⅳ/Ⅰ~Ⅱ) 139 5.783 2.862~11.682 0.000 4.445 2.437~8.106 0.000
组织学分期(Ⅲ/Ⅰ~Ⅱ) 98 3.350 1.699~6.606 0.000 4.150 2.185~7.880 0.000
DJ-1(阳性/阴性) 145 2.014 1.103~3.679 0.023 1.801 1.041~3.116 0.036
表4 多变量Cox 回归法分析临床病理参数与乳腺癌患者总生存及无瘤生存的相关性
变量 回归系数 标准误 Wald值 P值 RR值 95%CI
总生存
肿瘤直径(＞5.0 cm/≤5.0 cm) 0.697 0.424 2.708 0.100 2.008 0.875~4.606
淋巴结转移(是/否) 1.727 0.628 7.551 0.006 5.623 1.641~19.269
TNM分期(Ⅲ~Ⅳ/Ⅰ~Ⅱ) 0.478 0.471 1.032 0.310 1.614 0.641~4.062
组织学分期(Ⅲ/Ⅰ~Ⅱ) 0.512 0.369 1.926 0.165 1.668 0.810~3.435
DJ-1(阳性/阴性) 0.209 0.360 0.337 0.561 1.233 0.608~2.499
无瘤生存
肿瘤直径(＞5.0 cm/≤5.0 cm) 0.251 0.393 0.407 0.523 1.285 0.595~2.779
淋巴结转移(是/否) 1.426 0.547 6.790 0.009 4.161 1.424~12.161
TNM分期(Ⅲ~Ⅳ/Ⅱ~Ⅱ) 0.513 0.421 1.482 0.224 1.670 0.731~3.811
组织学分期(Ⅲ/Ⅰ~Ⅱ) 0.879 0.341 6.650 0.010 2.410 1.235~4.702
DJ-1(阳性/阴性) 0.318 0.334 0.903 0.342 1.374 0.714~2.645
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