Expression of serum keratin fragment 19 in patients with gastric cancer and its predictive power for positive HER-2
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摘要:
背景 HER-2阳性的胃癌患者预后较差，且缺少与胃癌HER-2阳性相关肿瘤标志物的报道。 目的 探讨血清CYFRA21-1表达水平与HER-2阳性胃癌患者的相关性。 方法 收集2019年1月 - 2021年12月在解放军总医院手术治疗的胃癌患者165例，其中男115例，女50例，年龄29 ~ 82岁。分析HER-2基因表达阳性患者的CYFRA21-1水平，并绘制CYFRA21-1在HER-2阳性患者中表达的ROC曲线，分析其预测HER-2阳性胃癌的阈值。 结果 血清CYFRA21-1水平与胃癌的病理组织学分化程度和分型、TNM分期及肿瘤大小有关(P＜0.05）；HER-2阳性组中CYFRA21-1水平显著高于阴性组(P=0.038)；CYFRA21-1阳性表达在HER-2阳性组中的OR值为3.529(95% CI：0.967 ~ 12.878)，对HER-2阳性胃癌患者的预测百分比为70.4%，当CYFRA21-1的Cut-off值为3.62 ng/mL时，对胃癌患者HER-2阳性的预测敏感度和特异度达到最高，分别为0.552和0.833。CYFRA21-1＜3.62 ng/mL的胃癌患者1年、2年、3年生存率高于CYFRA21-1＞3.62 ng/mL者(P=0.002)，HER-2阴性胃癌患者1年、2年、3年生存率高于阳性者(P=0.044)。 结论 HER-2基因及血清CYFRA21-1水平在胃癌转移、肿瘤较大、TNM分期较晚的患者中表达升高。CYFRA21-1水平较高、HER-2阳性者生存预后较差。高血清CYFRA21-1水平对胃癌患者HER-2基因阳性表达有一定的预测价值。 -
关键词:
- 人类表皮生长因子受体2 /
- 细胞角质素片段19 /
- 胃癌 /
- TNM分期 /
- 肿瘤标志物
Abstract:Background The prognosis of gastric cancer patients with positive HER-2 is poor, and there is a lack of reports on tumor markers related to positive HER-2 in gastric cancer. Objective To investigate the correlation between serum CYFRA21-1 expression and HER-2 positive gastric cancer patients. Methods From January 2019 to December 2021, 165 gastric cancer patients, including 115 males and 50 females, aged from 29 to 82 years, were enrolled in this study. The CYFRA21-1 level of patients with positive HER-2 gene expression was analyzed. The ROC curve of CYFRA21-1 expression in HER-2 positive patients was drawn to analyze the threshold of predicting HER-2 positive gastric cancer. Results Serum CYFRA21-1 level was correlated with histopathological differentiation and classification of gastric cancer, TNM stage and tumor size (P<0.05). The level of CYFRA21-1 in HER-2 positive group was significantly higher than that in negative group (P=0.038). The OR value of CYFRA21-1 in the positive HER-2 group was 3.529 (0.967-12.878), and the prediction percentage of positive HER-2 gastric cancer patients was 70.4%. When the cutoff value of CYFRA21-1 was 3.60 ng/mL, the sensitivity and specificity of positive HER-2 prediction in gastric cancer patients would reach the highest, which were 0.552 and 0.833, respectively. The 1-year, 2-year and 3-year survival rates of gastric cancer patients with CYFRA21-1<3.62 ng/mL were higher than those with CYFRA21-1>3.62 ng/mL (P=0.0024). The 1-year, 2-year and 3-year survival rates of HER-2 negative gastric cancer patients were higher than those of positive patients (P=0.0442). Conclusion The expression levels of HER-2 gene and sera CYFRA21-1 increase in patients with gastric cancer metastasis, large tumor and late TNM stage. The survival prognosis of patients with high CYFRA21-1 level and positive HER-2 is poor. High sera CYFRA21-1 level has a good warning effect on positive HER-2 gene in gastric cancer patients. -
Key words:
- HER-2 /
- CYFRA21-1 /
- gastric cancer /
- TNM stage /
- tumor marker
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图 1 肿瘤标志物预测HER-2阳性胃癌患者的ROC曲线
Figure 1. ROC curves of tumor marker prediction in patients with HER-2 positive gastric cancer
图 2 不同CYFRA21-1水平及HER-2表达胃癌患者的生存曲线
Figure 2. Survival curves of gastric cancer patients with different CYFRA21-1 levels and HER-2 expression
表 1 HER-2阳性和阴性患者的临床基线资料及患者不同状态下HER-2表达(例，%)、CYFRA21-1水平[Md(IQR)]差异比较
Table 1. Baseline data of patients with positive or negative HER-2 and comparison of HER-2 expression (n, %) and CYFRA21-1 level (Md[IQR]) in patients under different conditions
分组 总数/例 HER-2 CYFRA211/(ng·mL-1) 阴性(n=51) 阳性(n=76) χ2值 P值 水平 U/H值 P值 性别 1.928 0.165 -0.738 0.460 男 115 40(38.26) 51(44.35) 2.95(2.35 ~ 5.89) 女 50 11(22.00) 25(50.00) 3.93(2.29 ~ 6.23) 年龄 0.397 0.529 -0.700 0.484 ＜60岁 69 23(33.33) 30(43.48) 2.76(1.92 ~ 5.82) ≥60岁 96 28(29.17) 46(47.92) 3.00(2.35 ~ 4.44) 分化程度 0.378 0.539 -2.031 0.042 高-中分化腺癌 74 22(29.73) 37(50.00) 2.56(1.98 ~ 4.45) 低分化腺癌-印戒细胞癌 89 29(32.58) 39(43.82) 3.25(2.41 ~ 4.50) Lauren分型 0.232 0.630 -0.627 0.530 肠型 56 23(41.07) 31(55.36) 2.83(2.24 ~ 4.73) 弥散型 + 混合型 90 28(31.11) 45(50.00) 3.14(2.37 ~ 4.48) Borrmann分型 4.651 0.031 -0.117 0.907 早癌 + 结节型 55 12(21.82) 32(58.18) 2.81(2.44 ~ 5.66) 溃疡型 + 弥漫型 110 39(35.45) 44(40.00) 3.21(2.28 ~ 4.45) TNM分期 1.984 0.371 11.291 0.004 Ⅰ 54 17(31.48) 26(48.15) 2.54(2.00 ~ 2.98) Ⅱ+Ⅲ 63 26(41.27) 29(46.03) 3.25(2.38 ~ 5.74) Ⅳ 34 7(20.59) 16(47.06) 4.09(3.22 ~ 6.79) 浸润程度(T) 2.521 0.471 9.077 0.028 黏膜层 50 12(24.00) 26(52.00) 2.56(2.05 ~ 2.87) 固有肌层 15 6(40.00) 6(40.00) 3.21(1.76 ~ 5.66) 浆膜层 44 16(36.36) 19(43.18) 3.00(2.29 ~ 4.50) 胃壁全层 34 15(44.12) 17(50.00) 4.09(3.29 ~ 6.79) 淋巴结转移(N) 5.131 0.274 -3.513 ＜0.001 无 69 25(36.23) 32(46.38) 2.52(1.92 ~ 3.16) 有 74 24(32.43) 33(44.59) 3.80(2.56 ~ 6.38) 远处转移(M) 1.824 0.177 -3.320 ＜0.001 无 118 43(36.44) 54(45.76) 2.70(2.23 ~ 4.27) 有 35 7(20.00) 17(48.57) 4.44(3.60 ~ 6.84) 肿瘤个数 1.047 0.306 -1.172 0.241 单个 133 47(35.34) 61(45.86) 3.10(2.36 ~ 4.45) 多个 10 2(20.00) 6(60.00) 2.34(1.66 ~ 7.21) 肿瘤大小 0.076 0.782 -4.111 ＜0.001 直径＜3 cm 86 28(32.56) 40(46.51) 2.56(1.97 ~ 3.14) 直径≥3 cm 56 21(37.50) 27(48.21) 4.38(3.25 ~ 6.78) 
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表 2 肿瘤标志物水平在HER-2阳性与阴性胃癌患者中的表达差异[Md(IQR)]
Table 2. Differences in the expression of tumor markers levels in patients with HER-2 positive or negative gastric cancer (Md[IQR])
变量 HER-2阴性
(n=51)HER-2阳性
(n=76)U值 P值 CEA/(μg·L-1) 2.39(1.60 ~ 3.37) 2.80(1.36 ~ 5.73) -1.810 0.070 AFP/(μg·L-1) 2.97(1.93 ~ 3.78) 2.67(2.37 ~ 3.03) -0.234 0.815 CA19-9/(U·mL-1) 8.87(6.38 ~ 11.11) 10.25(6.30 ~ 25.34) -1.195 0.232 CA15-3/(U·mL-1) 7.65(6.37 ~ 10.94) 9.34(6.81 ~ 12.45) -1.820 0.069 CA724/(U·mL-1) 2.35(1.20 ~ 3.99) 3.19(1.41 ~ 9.96) -1.006 0.314 CYFRA21-1/(ng·mL-1) 2.38(2.20 ~ 3.38) 3.91(2.57 ~ 6.60) -2.073 0.038 NSE/(ng·mL-1) 11.66(9.84 ~ 16.53) 12.50(9.48 ~ 15.24) -0.909 0.364 SCC/(ng·mL-1) 0.90(0.70 ~ 1.30) 0.85(0.70 ~ 1.03) -0.156 0.876 PGⅠ/(ng·mL-1) 47.10(29.00 ~ 73.80) 53.80(33.80 ~ 111.88) -1.009 0.313 PGⅡ/(ng·mL-1) 10.40(7.00 ~ 15.90) 15.55(8.50 ~ 23.73) -1.446 0.148 PGⅠ/Ⅱ 5.79(2.64 ~ 7.67) 4.03(2.39 ~ 6.34) -0.895 0.371
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表 3 HER-2表达与CYFRA21-1水平相关性分析
Table 3. Correlation analysis of HER-2 expression and CYFRA21-1 level
变量 CYFRA21-1 r值 P值 HER-2 0.251 0.037
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表 4 基于CYFRA211、CEA、CA153建立的二元logistic回归模型
Table 4. Binary logistic regression model based on CYFRA211
变量 B $S \bar x $ Wald Sig OR OR 95% CI CYFRA211 1.261 0.661 3.644 0.056 3.529 0.967 ~ 12.878 CEA 0.859 0.945 0.825 0.364 2.360 0.370 ~ 15.049 CA153 0.998 1.240 0.648 0.421 2.713 0.239 ~ 30.828 常数 -0.023 0.322 0.005 0.944 0.978 -
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表 5 血清肿瘤标志物预测HER-2阳性胃癌患者的效能
Table 5. Efficacy of serum tumor markers in predicting HER-2 positive gastric cancer patients
变量 敏感
度特异
度约登
指数截断
值P值 AUC 95% CI CEA 0.310 0.944 0.255 4.25 0.470 0.563 0.399 ~ 0.727 AFP 0.897 0.333 0.230 2.03 0.584 0.452 0.264 ~ 0.640 CA19-9 0.310 0.944 0.255 20.95 0.294 0.592 0.431 ~ 0.753 CA15-3 0.690 0.556 0.245 7.72 0.406 0.573 0.406 ~ 0.740 CA724 0.414 0.889 0.303 5.57 0.165 0.622 0.459 ~ 0.784 NSE 0.586 0.611 0.197 12.17 0.965 0.496 0.317 ~ 0.675 SCC 0.690 0.389 0.079 0.80 0.470 0.437 0.264 ~ 0.609 PGⅠ 0.345 0.889 0.234 88.70 0.375 0.578 0.407 ~ 0.748 PGⅡ 0.586 0.722 0.308 14.00 0.189 0.615 0.445 ~ 0.785 PGⅠ/Ⅱ 0.793 0.278 0.071 2.72 0.336 0.416 0.243 ~ 0.588 CYFRA21-1 0.552 0.833 0.385 3.62 0.020 0.704 0.548 ~ 0.860
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