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Predictive Value of Albumin-Bilirubin Score Combined with Liver Function Index and CEA for Liver Metastasis of Colorectal Cancer
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摘要:目的 探讨白蛋白-胆红素(albumin-bilirubin, ALBI)评分联合肝功能指标及癌胚抗原(carcinoembryonic antigen, CEA)对结直肠癌肝转移的预测价值。方法 回顾性分析2016年1月至2021年7月于兰州大学第二医院接受手术治疗且随访满24个月的结直肠癌患者临床资料, 依据随访结果将入组患者分为肝转移组和非肝转移组, 并按2∶1比例随机分为建模组与验证组。分析结直肠癌患者发生肝转移的风险因素, 采用Lasso-Logistic回归构建预测模型, 采用Bootstrap法进行内部验证, 应用受试者工作特征曲线、校准曲线和临床决策曲线评价预测模型的可靠性, 最后绘制列线图展示预测结果。结果 共入选符合纳入和排除标准的结直肠癌患者195例, 其中建模组130例, 验证组65例; Lasso回归变量筛选及Logistic回归分析结果显示, ALBI评分(OR=8.062, 95% CI: 2.545~25.540)、丙氨酸氨基转移酶(alanine transaminase, ALT)(OR=1.037, 95% CI: 1.004~1.071)与CEA(OR=1.025, 95% CI: 1.008~1.043)是结直肠癌发生肝转移的独立预测因素; 建模组三者联合预测结直肠癌发生肝转移的曲线下面积(area under the curve, AUC)为0.921, 灵敏度为78.0%, 特异度为95.0%, C-index为0.921, H-L拟合度曲线χ2=0.851, P=0.654, 校准曲线斜率接近1, 提示该模型准确度较高, 临床决策曲线显示该模型具有良好的临床应用价值。对建模组数据采用Bootstrap法进行1000次重抽样的内部验证, 准确度为0.869, Kappa一致性为0.709, AUC为0.913;应用ALBI评分、ALT与CEA单独诊断结直肠癌肝转移时, CEA的AUC最大(0.897), 三者联合诊断结直肠癌肝转移的效能最高。验证组三者联合预测结直肠癌发生肝转移的AUC为0.918, 灵敏度为85.0%, 特异度为95.6%, C-index为0.918, H-L拟合度曲线χ2=0.586, P=0.746。结论 ALBI评分、ALT与CEA对结直肠癌肝转移具有一定预测价值, 三者联合预测结直肠癌肝转移的效能较高, 通过其构建的风险预测模型具有良好的临床应用前景。Abstract:Objective To investigate the predictive value of albumin-bilirubin (ALBI) score combined with liver function index and carcinoembryonic antigen (CEA) for liver metastasis of colorectal cancer.Methods We retrospectively analyzed the clinical data of patients with colorectal cancer who underwent surgical treatment in the Second Hospital & Clinical Medical Hospital, Lanzhou University from January 2016 to July 2021 and were followed up for 24 months. According to the follow-up results, the enrolled patients were divided into liver metastasis group and non-liver metastasis group, and were randomly divided into modeling group and validation group by a ratio of 2∶1. The risk factors of liver metastasis in the patients with colorectal cancer were analyzed. Lasso-Logistic regression was used to construct the prediction model. Bootstrap method was used for internal verification. Receiver operating characteristic curve, calibration curve and clinical decision curve were used to evaluate the reliability of the prediction model. Finally, a nomogram was drawn to show the prediction results.Results A total of 195 patients who met the inclusion and exclusion criteria were enrolled, including 130 in the modeling group and 65 in the validation group. Through Lasso regression variable screening and Logistic regression analysis, the results showed that ALBI score(OR=8.062, 95% CI: 2.545-25.540), alanine transaminase (ALT) (OR=1.037, 95% CI: 1.004-1.071) and CEA (OR=1.025, 95% CI: 1.008-1.043) were independent predictors of liver metastasis in colorectal cancer. The area under curve (AUC) of the combined prediction of liver metastasis of colorectal cancer in the modeling group was 0.921, the sensitivity was 78%, the specificity was 95%, the C-index was 0.921, the H-L fitting curve χ2=0.851, P=0.654, and the slope of the calibration curve was close to 1, suggesting that the accuracy of the model was high, and the DCA curve showed that the model had good clinical application value. For the data of the modeling group, the Bootstrap method was used for internal verification of 1000 resamplings. The accuracy was 0.869, the kappa consistency was 0.709, and the AUC was 0.913. When ALBI score, ALT and CEA were used to diagnose liver metastasis of colorectal cancer alone, the AUC of CEA was the largest (0.897), and the combination of the three had the highest efficacy in the diagnosis of liver metastasis of colorectal cancer. In the validation group, the AUC, sensitivity, specificity, C-index of the combined prediction of liver metastasis of colorectal cancer were 0.918, 85.0%, 95.6%, 0.918, respectively, and H-L fitting curve χ2=0.586, P=0.746.Conclusions ALBI score, ALT and CEA have certain predictive value for liver metastasis of colorectal cancer. The combined diagnosis of liver metastasis of colorectal cancer has high efficacy, and the risk prediction model constructed has a good predictive effect.
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Keywords:
- albumin-bilirubin score /
- CEA /
- colorectal cancer /
- liver metastasis /
- predictive value
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胃肠间质瘤(gastrointestinal stromal tumors，GISTs)是胃肠道最常见的间叶组织肿瘤, 起源于消化道肌层Cajal细胞(interstitial cells of Cajal，ICCs)或其同源干细胞[1]，可发生于胃肠道任何部位，大多数位于胃(70%)和小肠(10%~25%)[2]，少数位于直肠、食管及结肠[3]。其发病率约为(1~2)/10万，占胃肠道肿瘤的1%~3%，胃肠道肉瘤的80%[4]，但近年来呈明显上升趋势[5]。GISTs生长缓慢、症状隐匿、临床表现多样、无特异性，早期诊断极为困难，误诊率高达91.7%[6]，故发现时多为中晚期，直接影响治疗效果及预后。此外，GISTs对传统放化疗并不敏感，手术完整切除是唯一可能治愈的方法，但仍有40%~80%的GISTs于术后19~25个月出现复发、转移[7]。
大部分GISTs的发生与KIT和/或PDGFRA基因功能性突变有关[8-10]。酪氨酸激酶受体抑制剂使GISTs治疗取得了革命性进展，但仍有14%的GISTs原发耐药[11]。另外，由于两基因存在多位点和/或二次突变, 导致靶向治疗耐药率及复发率逐年升高，成为影响疗效的关键因素。研究发现，术后服用伊马替尼(imatinib)的GISTs患者中位无进展生存期约为2年，2年内继发耐药率为40%~50%。舒尼替尼(sunitinib)对伊马替尼耐药病例疾病控制率仅为65%(7%有效，58%疾病无进展)，且持续时间短，易耐药[12]。regorafenib、sorafenib等均对一线、二线耐药的GISTs效果尚不确切且不良反应多[13]。因此，GISTs的治疗面临着瓶颈制约，寻找新的治疗方法成为当前GISTs治疗研究热点。
1. 胃肠间质瘤与ETV1表达
KIT基因编码Ⅲ型酪氨酸激酶家族跨膜受体。正常情况下，c-kit蛋白必须与配体——干细胞因子结合，发生自身磷酸化，激活有丝分裂活化蛋白激酶和磷脂酰肌醇3激酶，进而激发激酶磷酸化链式反应，促进细胞增殖。c-kit基因突变后，其蛋白活化不再受配体限制，表现为持续、自动磷酸化，使c-kit信号转导系统病态增强，促使细胞增殖并抑制凋亡，最终导致肿瘤形成[14-15]。
ETS转录家族有30多个成员，是目前最大的信号依赖转录调控因子家族之一。这些信号分子拥有由85个氨基酸组成的特异DNA结合区，可与靶基因启动区(一般为富含嘌呤序列GGAA/T)结合，调控靶基因转录，参与肿瘤发生、演进[16-17]。ETV1位于染色体7p21.2, 是ETS家族PEA3亚科转录因子。ETV1可结合的靶基因较多，通过调节靶基因的表达, 在调控肿瘤细胞增殖、分化、迁移中起重要作用。研究表明，ETV1在肿瘤组织中如前列腺癌、黑色素瘤、乳腺癌中表达量较正常组织显著升高[18-22]。
ETV1在GISTs肿瘤组织及GISTs细胞株中均呈高表达, 且显著高于其他肿瘤。GISTs细胞株中，ETV1对靶基因的作用由复杂的调控网络调节，其中，Ras/Raf/MAPK信号通路是调控ETV1的主要通路[23-25]。GISTs患者中联合使用伊马替尼与MEK抑制剂，GISTs生长会受到明显抑制。研究发现[26]，ETV1表达与KIT基因转录呈正反馈循环：ETV1可刺激KIT基因转录，KIT蛋白促进ETV1表达，且增强ETV1稳定性，减缓降解。ICCs转变为GISTs过程由KIT基因与ETV1协调配合实现，即KIT基因功能性突变和ETV1变化同步、协调进行，从而导致GISTs的发生[27]。阻断ETV1基因表达后, 细胞分裂减少、凋亡增加, 表明ETV1对GISTs发生、发展起至关重要的作用。另有研究表明[28]，ETV1对于野生型GISTs尚有辅助诊断的作用, 且ETV1表达可能作为GISTs患者根治术后3年无病生存率的评估指标。
综上所述，ETV1可能与GISTs发生、发展相关，但能否将ETV1作为耐药性GISTs治疗新靶点，ETV1可否作为评估GISTs恶性程度、预测肿瘤进展的指标仍有待基础、临床进一步研究。深入探索ETV1在GISTs发生、发展中可能的作用机制，将为GISTs诊疗提供更多思路。
2. 胃肠间质瘤与FOXF1表达
FOX基因家族属于叉头框(forkhead box)基因, 在分子结构上具有明显的叉头DNA结合区[29]，共包含19个亚族, 50个成员，功能涉及胚胎发育、细胞周期调控、糖类/脂类代谢、免疫调节、衰老等多种生物过程。FOX家族基因在人体内主要发挥转录因子的作用, 调控多种靶基因表达，与肿瘤发展、侵袭、转移密切相关[30]。FOXF1基因是FOX基因家族中的一员，位于人类染色体16q24.1, 编码FOXF1转录因子。FOXF1能抑制肿瘤细胞增殖、转移, 其失活会促进肿瘤进展，表现为促瘤效应[31]。研究表明[32]，在所有入组的GISTs组织中，无论KIT/PDGFRA突变状况如何，FOXF1均为阳性表达。这说明FOXF1可能在GISTs中普遍表达，但在其他肉瘤中很少观察到FOXF1表达。即FOXF1在GISTs中普遍表达，且具有相对特异性。因此FOXF1可能成为GISTs敏感的、具有一定特异性的新型分子标志物。
3. FOXF1与ETV1
研究发现[32]，FOXF1可能是ETV1的上游调节因子，FOXF1主要结合位点是增强子，通过与增强子结合后调控KIT、ETV1表达，进而调节GISTs发生及发展。FOXF1下调不仅导致ICCs/GISTs谱系基因转录减少，且ETV1表达也呈下降趋势。用伊马替尼抑制KIT及其下游MAPK通路信号转导，或MEK162(MEK抑制剂)对MAPK信号通路进行短期抑制后，均可导致ETV1蛋白降解。上述通路重新激活后，ETV1蛋白水平也相应恢复[33-34]。整个过程中，FOXF1蛋白表达水平无显著波动，即FOXF1直接影响ETV1的表达，但ETV1变化并未对FOXF1造成明显影响。这些发现表明，FOXF1可能位于GISTs生长信号分子ETV1上游，调控ETV1的表达。但FOXF1在GISTs中表达的意义、与GISTs病理特征相关性、是否可作为GISTs治疗新方向，目前尚无相关研究进行探究。
4. 小结
FOXF1、ETV1、KIT三者在GISTs生长调控中的作用可表述为FOXF1位于信号通路的最上游，可正向调控ETV1表达，ETV1继而调控KIT表达，且二者形成正反馈。这表明，FOXF1、ETV1很有可能是GISTs药物治疗的新靶点，为处于治疗瓶颈中的GISTs患者带来新的希望。但如何以FOXF1、ETV1为靶点开发治疗的GISTs药物，尤其是多重耐药GISTs，仍需更大样本、前瞻性基础、临床研究进一步探索。
作者贡献：樊万里负责资料收集和论文撰写；何栋、张树泽、陈刚、赵斌提供论文撰写意见；程志斌负责论文设计及审校。利益冲突：所有作者均声明不存在利益冲突 -
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图 2 基于Lasso回归的特征变量筛选
A.十倍交叉验证图; B.收缩系数图
Figure 2. Feature variable selection based on Lasso regression
A.Ten fold cross validation chart; B.Shrinkage coefficient chart
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图 3 模型预测结直肠癌肝转移的受试者工作特征曲线
A.建模组；B.验证组
Figure 3. Receiver operating characteristic curve of the model predicting liver metastasis of colorectal cancer
A.Modeling group; B.Verification group
ALT、CEA、ALBI: 同表 1![]()
图 4 Lasso-Logistic回归模型校准曲线
A.建模组；B.验证组
Figure 4. Calibration curves of the Lasso-Logistic regression model
A.Modeling group; B.Verification group
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图 5 Lasso-Logistic回归模型临床决策曲线
A.建模组；B.验证组
Figure 5. Decision curve analysis of the Lasso-Logistic regression model
B.Modeling group; B.Verification group
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图 6 结直肠癌肝转移的列线图预测模型
ALT、CEA、ALBI: 同表 1
Figure 6. Nomogram prediction model for liver metastasis of colorectal cancer
表 1 肝转移组与非肝转移组的基线资料比较(n=195)
Table 1 Baseline data between liver metastasis group and non-liver metastasis group(n=195)
指标 肝转移组(n=70) 非肝转移组(n=125) P值 年龄(x±s，岁) 58.3±12.5 61.7±12.0 0.067 性别[n(%)] 0.865 男 40(57.1) 73(58.4) 女 30(42.9) 52(41.6) 原发肿瘤位置[n(%)] 0.042 结肠 38(54.3) 49(39.2) 直肠 32(45.7) 76(60.8) BMI[M(P25, P75), kg/m2] 22.5(21.4, 24.7) 22.1(20.2, 25.0) 0.280 TBIL[M(P25, P75), μmol/L] 14.9(11.6, 24.7) 12.8(9.4, 16.9) 0.001 DBIL[M(P25, P75), μmol/L] 7.2(4.3, 10.6) 3.3(2.3, 5.4) ＜0.001 IBIL[M(P25, P75), μmol/L] 9.3(5.2, 14.3) 8.8(6.0, 12.1) 0.642 ALT[M(P25, P75), U/L] 31.5(16.0, 54.8) 17.0(10.0, 25.0) ＜0.001 AST[M(P25, P75), U/L] 40.0(27.8, 87.3) 20.0(16.0, 25.5) ＜0.001 AST/ALT[M(P25, P75)] 1.6(1.1, 2.2) 1.4(0.9, 1.7) 0.005 TP[M(P25, P75), g/L] 65.1(58.9, 70.6) 69.4(64.3, 73.4) 0.001 ALB[M(P25, P75), g/L] 36.3(29.5, 40.2) 41.4(38.3, 44.1) ＜0.001 GLO[M(P25, P75), g/L] 29.3(24.7, 33.5) 28.3(24.0, 31.0) 0.124 A/G(x±s) 1.2±0.4 1.5±0.3 ＜0.001 GGT[M(P25, P75), U/L] 59.0(25.8, 148.0) 18.0(13.0, 25.5) ＜0.001 ALP[M(P25, P75), U/L] 122.5(77.5, 211.0) 76.0(63.0, 90.5) ＜0.001 AFP[M(P25, P75), μg/L] 2.6(1.6, 3.4) 2.5(1.8, 3.2) 0.845 CEA[M(P25, P75), μg/L] 79.5(12.5, 476.0) 2.9(1.8, 5.9) ＜0.001 CA125[M(P25, P75), U/mL] 21.3(11.0, 54.7) 11.1(7.9, 16.7) ＜0.001 CA19-9[M(P25, P75), U/mL] 85.5(17.3, 801.7) 10.9(7.5, 17.0) ＜0.001 ALBI评分[M(P25, P75), 分] -2.3(-2.7, -1.6) -2.8(-3.0, -2.6) ＜0.001 BMI(body mass index)：体质量指数；TBIL(total bilirubin)：总胆红素；DBIL(direct bilirubin)：直接胆红素；IBIL(indirect bilirubin)：间接胆红素；ALT(alanine transaminase)：丙氨酸氨基转移酶；AST(aspartate transaminase)：天冬氨酸氨基转移酶；TP(total protein)：总蛋白；ALB(albumin)：白蛋白；GLO(globulin): 球蛋白；A/G(albumin/globulin)：白球比；GGT(γ-glutamyle transpeptidase)：γ-谷氨酰转移酶；ALP(alkaline phosphatase)：碱性磷酸酶；AFP(alpha fetoprotein)：甲胎蛋白；CEA(carcinoembryonic antigen)：癌胚抗原；CA125(carbohydrate antigen 125)：糖类抗原125；CA19-9(carbohydrate antigen19-9)：糖类抗原19-9；ALBI(albumin-bilirubin)：白蛋白-胆红素 
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表 2 建模组与验证组的基线资料比较(n=195)
Table 2 Baseline data between modeling group and validation group(n=195)
指标 建模组(n=130) 验证组(n=65) P值 年龄(x±s，岁) 60.3±11.8 60.8±13.2 0.770 性别[n(%)] 0.473 男 73(56.2) 40(61.5) 女 57(43.8) 25(38.5) 原发肿瘤位置[n(%)] 0.222 结肠 62(47.7) 25(38.5) 直肠 68(52.3) 40(61.5) BMI[M(P25, P75), kg/m2] 22.3(20.3, 24.9) 22.0(20.6, 25.0) 0.992 TBIL[M(P25, P75), μmol/L] 13.3(10.2, 18.0) 14.0(9.6, 18.7) 0.825 DBIL[M(P25, P75), μmol/L] 4.7(2.8, 7.3) 3.9(2.7, 7.1) 0.462 IBIL[M(P25, P75), μmol/L] 8.7(5.5, 11.9) 9.6(5.6, 13.0) 0.412 ALT[M(P25, P75), U/L] 17.5(11.0, 31.0) 20.0(11.0, 33.0) 0.518 AST[M(P25, P75), U/L] 24.5(17.0, 36.0) 24.0(17.5, 38.0) 0.846 AST/ALT[M(P25, P75)] 1.4(0.9, 1.8) 1.4(0.9, 1.9) 0.715 TP[M(P25, P75), g/L] 68.3(63.8, 72.9) 67.1(61.8, 73.0) 0.348 ALB[M(P25, P75), g/L] 40.1(35.8, 43.5) 39.1(36.8, 42.7) 0.666 GLO[M(P25, P75), g/L] 28.7(24.4, 32.4) 28.4(24.0, 31.4) 0.556 A/G(x±s) 1.4±0.4 1.4±0.3 0.990 GGT[M(P25, P75), U/L] 22.5(14.0, 51.3) 22.0(14.5, 40.5) 0.828 ALP[M(P25, P75), U/L] 80.0(63.8, 111.0) 86.0(67.0, 110.0) 0.606 AFP[M(P25, P75), μg/L] 2.5(1.7, 3.3) 2.7(1.6, 3.2) 0.607 CEA[M(P25, P75), μg/L] 4.7(2.0, 33.3) 5.3(2.5, 35.3) 0.514 CA125[M(P25, P75), U/mL] 12.6(8.6, 23.2) 13.2(9.1, 22.7) 0.790 CA19-9[M(P25, P75), U/mL] 13.9(8.1, 52.6) 15.2(8.2, 52.4) 0.697 ALBI评分[M(P25, P75), 分] -2.7(-2.9, -2.3) -2.7(-2.9, -2.4) 0.522 BMI、TBIL、DBIL、IBIL、ALT、AST、TP、ALB、GLO、A/G、GGT、ALP、AFP、CEA、CA125、CA19-9、ALBI：同表 1
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表 3 结直肠癌肝转移影响因素的多因素Logistic回归分析结果
Table 3 Multivariate Logistic regression analysis results of factors influencing liver metastasis of colorectal cancer
变量 β 标准误差 Wald 自由度 P值 OR 95% CI 下限 上限 ALT(U/L) 0.036 0.017 4.734 1 0.030 1.037 1.004 1.071 CEA(μg/L) 0.025 0.009 8.017 1 0.005 1.025 1.008 1.043 ALBI评分(分) 2.087 0.588 12.588 1 0.000 8.062 2.545 25.540 常数项 3.047 1.555 3.839 1 0.050 21.058 - ALT、CEA、ALBI：同表 1
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表 4 建模组患者ALT、CEA和ALBI评分单独检测与联合检测的诊断效能比较
Table 4 Diagnostic efficacy between individual and combined detection of ALT, CEA, and ALBI score in modeling group
检测指标 AUC 灵敏度(%) 特异度(%) P值 ALT 0.704 58.0 85.0 ＜0.001 CEA 0.897 84.0 87.5 ＜0.001 ALBI评分 0.825 84.0 72.5 ＜0.001 ALT联合CEA 0.896 80.0 91.2 ＜0.001 ALT联合ALBI评分 0.858 80.0 78.7 ＜0.001 CEA联合ALBI评分 0.911 82.0 86.3 ＜0.001 三者联合 0.921 78.0 95.0 ＜0.001 ALT、CEA、ALBI：同表 1；AUC(area under the curve)：曲线下面积
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表 5 验证组患者ALT、CEA和ALBI评分单独检测与联合检测的诊断效能比较
Table 5 Diagnostic efficacy between individual and combined detection of ALT, CEA, and ALBI score in verification group
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