基于TCGA数据库对RUVBL1基因在结肠腺癌中的诊断和预后价值研究
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摘要
目的通过对癌症基因组图谱(TCGA)数据库中结肠腺癌(colon adenocarcinoma,COAD)患者癌组织和癌旁正常结肠组织的RUVBL1基因RNA测序数据进行分析,研究其在结肠腺癌中的诊断和预后的价值。方法从TCGA数据库下载COAD的RNA测序数据集及临床资料,绘制散点图比较RUVBL1基因在COAD癌组织和癌旁正常组织中的表达差异;绘制ROC曲线研究RUVBL1基因表达对COAD的诊断价值;Kaplan-Meier法绘制生存曲线分析RUVBL1基因表达与COAD总体生存时间的关系;采用单因素与多因素Cox回归模型分析临床参数与COAD临床预后的关系,其中风险比(Hazard Ratio,HR)与95%置信区间(95%Confidence Interval,95%CI)用于量化评估临床参数与预后的相关性。结果 RUVBL1基因在癌组织中的表达量为(2486.000±39.590),高于其在癌旁正常结肠组织中的表达量(966.300±35.450),差异有统计学意义(P <0.001);ROC曲线显示RUVBL1基因对COAD有较高的诊断价值(AUC=0.972,95%CI:0.958～0.986);Kaplan-Meier生存曲线分析结果显示RUVBL1基因表达与总生存时间相关,低表达患者总体生存时间优于高表达患者(P=0.027);单因素分析结果显示患者性别、年龄与患者的预后无关(Log-rank P=0.545,0.114),而肿瘤TNM分期(P <0.001)、RUVBL1基因表达与COAD预后相关(Crude P=0.028;Crude HR=1.587,95%CI:1.051～2.397)。进一步进行校正肿瘤TNM分期的Cox多因素分析,结果显示RUVBL1基因高表达是影响COAD预后的独立危险因素(Adjusted P=0.038;Adjusted HR=1.565;95%CI:1.026～2.386)。结论 RUVBL1基因可能是COAD诊断和预测预后潜在的生物学标记物,未来需要更进一步研究来验证其价值。
Objectives To analyze the RUVBL1 gene RNA sequencing data of cancer tissue and adjacent normal tissue using the data from patients with colon adenocarcinoma(COAD) in the TCGA database, and to study its diagnostic and prognostic value in colon adenocarcinoma. Methods The RNA sequencing dataset and clinical data of COAD were downloaded from TCGA database. Scatterplots were used to compare expression of RUVBL1 gene in COAD cancer tissue and adjacent normal tissue. Receiver operating characteristic curve was used to investigate the value of RUVBL1 gene expression in diagnosing COAD. KaplanMeier analysis was used to investigate the correlation between RUVBL1 gene expression and overall survival time of COAD. Univariate and multivariate Cox regression model was used to analyze the effect of clinical characteristics on prognosis of COAD. Effect of each variable on prognosis was quantified by hazard ratio(HR) and 95% confidence interval(95% CI). Results RUVBL1 gene expression was(2486.000 ± 39.590) in cancer tissue, which was significantly higher than that(966.300 ± 35.450) in the adjacent normal tissue(P < 0.001). ROC curve showed favorable value of RUVBL1 gene in diagnosing COAD(AUC = 0.972, 95%CI: 0.958-0.986). Kaplan-Meier analysis showed significant correlation between RUVBL1 gene expression and overall survival time, with better overall survival in low expression than in high expression(P = 0.027). Univariate analysis showed that sex and age had no significant effect on patients' prognosis(Log-rank P = 0.545 and 0.114, respectively). TNM staging(P < 0.001)and RUVBL1 gene expression(Crude P = 0.028, Crude HR = 1.587, 95% CI: 1.051～2.397) had significant effect on prognosis.Multivariate Cox regression showed that after adjusting for TNM staging, high RUVBL1 gene expression was an independent factor influencing prognosis of COAD(adjusted P = 0.038, adjusted HR = 1.565, 95% CI: 1.026～2.386). Conclusion RUVBL1 gene might be a potential biomarker for diagnosis and prognosis of COAD. Further studies are required to verify its value.
Objectives To analyze the RUVBL1 gene RNA sequencing data of cancer tissue and adjacent normal tissue using the data from patients with colon adenocarcinoma(COAD) in the TCGA database, and to study its diagnostic and prognostic value in colon adenocarcinoma. Methods The RNA sequencing dataset and clinical data of COAD were downloaded from TCGA database. Scatterplots were used to compare expression of RUVBL1 gene in COAD cancer tissue and adjacent normal tissue. Receiver operating characteristic curve was used to investigate the value of RUVBL1 gene expression in diagnosing COAD. KaplanMeier analysis was used to investigate the correlation between RUVBL1 gene expression and overall survival time of COAD. Univariate and multivariate Cox regression model was used to analyze the effect of clinical characteristics on prognosis of COAD. Effect of each variable on prognosis was quantified by hazard ratio(HR) and 95% confidence interval(95% CI). Results RUVBL1 gene expression was(2486.000 ± 39.590) in cancer tissue, which was significantly higher than that(966.300 ± 35.450) in the adjacent normal tissue(P < 0.001). ROC curve showed favorable value of RUVBL1 gene in diagnosing COAD(AUC = 0.972, 95%CI: 0.958-0.986). Kaplan-Meier analysis showed significant correlation between RUVBL1 gene expression and overall survival time, with better overall survival in low expression than in high expression(P = 0.027). Univariate analysis showed that sex and age had no significant effect on patients' prognosis(Log-rank P = 0.545 and 0.114, respectively). TNM staging(P < 0.001)and RUVBL1 gene expression(Crude P = 0.028, Crude HR = 1.587, 95% CI: 1.051～2.397) had significant effect on prognosis.Multivariate Cox regression showed that after adjusting for TNM staging, high RUVBL1 gene expression was an independent factor influencing prognosis of COAD(adjusted P = 0.038, adjusted HR = 1.565, 95% CI: 1.026～2.386). Conclusion RUVBL1 gene might be a potential biomarker for diagnosis and prognosis of COAD. Further studies are required to verify its value.
引文
[1]BRAY F,FERLAY J,SOERJOMATARAM I,et al.Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2018,68(6):394-424.
[2]FERLAY J,COLOMBET M,SOERJOMATARAM I,et al.Estimating the global cancer incidence and mortality in 2018:GLO-BOCAN sources and methods[J].Int J Cancer,2019,144(8):1941-1953.
[3]GARCIA-LARSEN V,MORTON V,NORAT T,et al.Dietary patterns derived from principal component analysis(PCA)and risk of colorectal cancer:a systematic review and meta-analysis[J].Eur J Clin Nutr,2019,73(3):366-386.
[4]MAGALHAES B,PELETEIRO B,LUNET N.Dietary patterns and colorectal cancer:systematic review and meta-analysis[J].Eur J Cancer Prev,2012,21(1):15-23.
[5]KOZMAN M A,FISHER O M,REBOLLEDO B J,et al.CEAto peritoneal carcinomatosis index(PCI)ratio is prognostic in patients with colorectal cancer peritoneal carcinomatosis undergoing cytoreduction surgery and intraperitoneal chemotherapy:a retrospective cohort study[J].J Surg Oncol,2018,117(4):725-736.
[6]CHEN T,YU L,LI B,et al.Elevated preoperative carcinoembryonic antigen and vascular endothelial growth factor predict shorter survival in patients with sigmoid colon carcinoma[J].Clin Lab,2017,63(3):445-451.
[7]PENG Y,ZHAI Z,LI Z,et al.Role of blood tumor markers in predicting metastasis and local recurrence after curative resection of colon cancer[J].Int J Clin Exp Med,2015,8(1):982-990.
[8]HUANG E Y,CHANG J C,CHEN H H,et al.Carcinoembryonic antigen as a marker of radioresistance in colorectal cancer:a potential role of macrophages[J].BMC Cancer,2018,18(1):321.
[9]SHINKINS B,NICHOLSON B D,PRIMROSE J,et al.The diagnostic accuracy of a single CEA blood test in detecting colorectal cancer recurrence:results from the FACS trial[J].PLoS One,2017,12(3):e0171810.
[10]HUANG S C,HUANG S F,CHEN Y T,et al.Overexpression of mutl homolog 1 and muts homolog 2 proteins have reversed prognostic implications for stage I-II colon cancer patients[J].Biomed J,2017,40(1):39-48.
[11]ZHENG S,CHERNIACK A D,DEWAL N,et al.Comprehensive pan-genomic characterization of adrenocortical carcinoma[J].Cancer Cell,2016,30(2):363.
[12]MUZNY D M,BAINBRIDGE M N,CHANG K.Comprehensive molecular characterization of human colon and rectal cancer[J].Nature,2012,487(7407):330-337.
[13]ZHU G,LIAO X,HAN C,et al.ALDH1L1 variant rs2276724and mRNA expression predict post-operative clinical outcomes and are associated with TP53 expression in HBV-related hepatocellular carcinoma[J].Oncol Rep,2017,38(3):1451-1463.
[14]LIAO X,HUANG R,LIU X,et al.Distinct prognostic values of alcohol dehydrogenase m RNA expression in pancreatic adenocarcinoma[J].Onco Targets Ther,2017,10:3719-3732.
[15]CUNNING D,ATKIN W,LENZ H J,et al.Colorectal cancer[J].Lancet,2010,375(9719):1030-1047.
[16]陈孝平主编.外科学[M].2版(上册).北京:人民卫生出版社,2010:587.
[17]UCHIYAMA K,NAITO Y,YAGI N,et al.Selected reaction monitoring for colorectal cancer diagnosis using a set of five serum peptides identified by BLOTCHIP((R))-MS analysis[J].JGastroenterol,2018,53(11):1179-1185.
[18]CHEN J J,WANG A Q,CHEN Q Q.DNA methylation assay for colorectal carcinoma[J].Cancer Biol Med,2017,14(1):42-49.
[19]ABDULLA M H,VALLI-MOHAMMED M A,AL-KHAYAL K,et al.Cathepsin B expression in colorectal cancer in a middle east population:potential value as a tumor biomarker for late disease stages[J].Oncol Rep,2017,37(6):3175-3180.
[20]HASHIMOTO Y,ZUMWALT T J,GOEL A.DNA methylation patterns as noninvasive biomarkers and targets of epigenetic therapies in colorectal cancer[J].Epigenomics,2016,8(5):685-703.
[21]ZHANG A,SUN H,YAN G,et al.Metabolomics in diagnosis and biomarker discovery of colorectal cancer[J].Cancer Lett,2014,345(1):17-20.
[22]NI Y,XIE G,JIA W.Metabonomics of human colorectal cancer:new approaches for early diagnosis and biomarker discovery[J].J Proteome Res,2014,13(9):3857-3870.
[23]NAKAMURA Y,YOSHINO T.Clinical utility of analyzing circulating tumor DNA in patients with metastatic colorectal cancer[J].Oncologist,2018,23(11):1310-1318.
[24]FENG X,LIU J,GONG Y,et al.DNA repair protein XPA is differentially expressed in colorectal cancer and predicts better prognosis[J].Cancer Med,2018,7(6):2339-2349.
[25]LI J,YI C H,HU Y T,et al.TNM Staging of colorectal cancer should be reconsidered according to weighting of the Tstage:verification based on a 25-year follow-up[J].Medicine(Baltimore),2016,95(6):e2711.
[26]LI J,GUO B C,SUN L R,et al.TNM staging of colorectal cancer should be reconsidered by T stage weighting[J].World JGastroenterol,2014,20(17):5104-5112.
[27]LEA D,HALAND S,HAGLAND H R,et al.Accuracy of TNMstaging in colorectal cancer:a review of current culprits,the modern role of morphology and stepping-stones for improvements in the molecular era[J].Scand J Gastroenterol,2014,49(10):1153-1163.
[28]GRIGOLETTO A,LESTIENNE P,ROSENBAUM J.The multifaceted proteins reptin and pontin as major players in cancer[J].Biochim Biophys Acta,2011,1815(2):147-157.
[29]MATIAS P M,BAEK S H,BANDEIRAS T M,et al.The AAA+proteins pontin and reptin enter adult age:from understanding their basic biology to the identification of selective inhibitors[J].Front Mol Biosci,2015,2:17.
[30]FAN W,XIE J,XIA J,et al.RUVBL1-ITFG1 interaction is required for collective invasion in breast cancer[J].Biochim Biophys Acta Gen Subj,2017,1861(7):1788-1800.
[31]GUO H,ZHANG X Y,PENG J,et al.RUVBL1,a novel C-RAF-binding protein,activates the RAF/MEK/ERK pathway to promote lung cancer tumorigenesis[J].Biochem Biophys Res Commun,2018,498(4):932-939.
[32]MIKESCH J H,HARTMANN W,ANGENENDT L,et al.AAA+ATPases reptin and pontin as potential diagnostic and prognostic biomarkers in salivary gland cancer-a short report[J].Cell Oncol(Dordr),2018,41(4):455-462.
[33]TANIUCHI K,FURIHATA M,IWASAKI S,et al.RUVBL1 directly binds actin filaments and induces formation of cell protrusions to promote pancreatic cancer cell invasion[J].Int J Oncol,2014,44(6):1945-1954.
[34]LAUSCHER J C,ELEZKURTAJ S,DULLAT S,et al.Increased pontin expression is a potential predictor for outcome in sporadic colorectal carcinoma[J].Oncol Rep,2012,28(5):1619-1624.
[2]FERLAY J,COLOMBET M,SOERJOMATARAM I,et al.Estimating the global cancer incidence and mortality in 2018:GLO-BOCAN sources and methods[J].Int J Cancer,2019,144(8):1941-1953.
[3]GARCIA-LARSEN V,MORTON V,NORAT T,et al.Dietary patterns derived from principal component analysis(PCA)and risk of colorectal cancer:a systematic review and meta-analysis[J].Eur J Clin Nutr,2019,73(3):366-386.
[4]MAGALHAES B,PELETEIRO B,LUNET N.Dietary patterns and colorectal cancer:systematic review and meta-analysis[J].Eur J Cancer Prev,2012,21(1):15-23.
[5]KOZMAN M A,FISHER O M,REBOLLEDO B J,et al.CEAto peritoneal carcinomatosis index(PCI)ratio is prognostic in patients with colorectal cancer peritoneal carcinomatosis undergoing cytoreduction surgery and intraperitoneal chemotherapy:a retrospective cohort study[J].J Surg Oncol,2018,117(4):725-736.
[6]CHEN T,YU L,LI B,et al.Elevated preoperative carcinoembryonic antigen and vascular endothelial growth factor predict shorter survival in patients with sigmoid colon carcinoma[J].Clin Lab,2017,63(3):445-451.
[7]PENG Y,ZHAI Z,LI Z,et al.Role of blood tumor markers in predicting metastasis and local recurrence after curative resection of colon cancer[J].Int J Clin Exp Med,2015,8(1):982-990.
[8]HUANG E Y,CHANG J C,CHEN H H,et al.Carcinoembryonic antigen as a marker of radioresistance in colorectal cancer:a potential role of macrophages[J].BMC Cancer,2018,18(1):321.
[9]SHINKINS B,NICHOLSON B D,PRIMROSE J,et al.The diagnostic accuracy of a single CEA blood test in detecting colorectal cancer recurrence:results from the FACS trial[J].PLoS One,2017,12(3):e0171810.
[10]HUANG S C,HUANG S F,CHEN Y T,et al.Overexpression of mutl homolog 1 and muts homolog 2 proteins have reversed prognostic implications for stage I-II colon cancer patients[J].Biomed J,2017,40(1):39-48.
[11]ZHENG S,CHERNIACK A D,DEWAL N,et al.Comprehensive pan-genomic characterization of adrenocortical carcinoma[J].Cancer Cell,2016,30(2):363.
[12]MUZNY D M,BAINBRIDGE M N,CHANG K.Comprehensive molecular characterization of human colon and rectal cancer[J].Nature,2012,487(7407):330-337.
[13]ZHU G,LIAO X,HAN C,et al.ALDH1L1 variant rs2276724and mRNA expression predict post-operative clinical outcomes and are associated with TP53 expression in HBV-related hepatocellular carcinoma[J].Oncol Rep,2017,38(3):1451-1463.
[14]LIAO X,HUANG R,LIU X,et al.Distinct prognostic values of alcohol dehydrogenase m RNA expression in pancreatic adenocarcinoma[J].Onco Targets Ther,2017,10:3719-3732.
[15]CUNNING D,ATKIN W,LENZ H J,et al.Colorectal cancer[J].Lancet,2010,375(9719):1030-1047.
[16]陈孝平主编.外科学[M].2版(上册).北京:人民卫生出版社,2010:587.
[17]UCHIYAMA K,NAITO Y,YAGI N,et al.Selected reaction monitoring for colorectal cancer diagnosis using a set of five serum peptides identified by BLOTCHIP((R))-MS analysis[J].JGastroenterol,2018,53(11):1179-1185.
[18]CHEN J J,WANG A Q,CHEN Q Q.DNA methylation assay for colorectal carcinoma[J].Cancer Biol Med,2017,14(1):42-49.
[19]ABDULLA M H,VALLI-MOHAMMED M A,AL-KHAYAL K,et al.Cathepsin B expression in colorectal cancer in a middle east population:potential value as a tumor biomarker for late disease stages[J].Oncol Rep,2017,37(6):3175-3180.
[20]HASHIMOTO Y,ZUMWALT T J,GOEL A.DNA methylation patterns as noninvasive biomarkers and targets of epigenetic therapies in colorectal cancer[J].Epigenomics,2016,8(5):685-703.
[21]ZHANG A,SUN H,YAN G,et al.Metabolomics in diagnosis and biomarker discovery of colorectal cancer[J].Cancer Lett,2014,345(1):17-20.
[22]NI Y,XIE G,JIA W.Metabonomics of human colorectal cancer:new approaches for early diagnosis and biomarker discovery[J].J Proteome Res,2014,13(9):3857-3870.
[23]NAKAMURA Y,YOSHINO T.Clinical utility of analyzing circulating tumor DNA in patients with metastatic colorectal cancer[J].Oncologist,2018,23(11):1310-1318.
[24]FENG X,LIU J,GONG Y,et al.DNA repair protein XPA is differentially expressed in colorectal cancer and predicts better prognosis[J].Cancer Med,2018,7(6):2339-2349.
[25]LI J,YI C H,HU Y T,et al.TNM Staging of colorectal cancer should be reconsidered according to weighting of the Tstage:verification based on a 25-year follow-up[J].Medicine(Baltimore),2016,95(6):e2711.
[26]LI J,GUO B C,SUN L R,et al.TNM staging of colorectal cancer should be reconsidered by T stage weighting[J].World JGastroenterol,2014,20(17):5104-5112.
[27]LEA D,HALAND S,HAGLAND H R,et al.Accuracy of TNMstaging in colorectal cancer:a review of current culprits,the modern role of morphology and stepping-stones for improvements in the molecular era[J].Scand J Gastroenterol,2014,49(10):1153-1163.
[28]GRIGOLETTO A,LESTIENNE P,ROSENBAUM J.The multifaceted proteins reptin and pontin as major players in cancer[J].Biochim Biophys Acta,2011,1815(2):147-157.
[29]MATIAS P M,BAEK S H,BANDEIRAS T M,et al.The AAA+proteins pontin and reptin enter adult age:from understanding their basic biology to the identification of selective inhibitors[J].Front Mol Biosci,2015,2:17.
[30]FAN W,XIE J,XIA J,et al.RUVBL1-ITFG1 interaction is required for collective invasion in breast cancer[J].Biochim Biophys Acta Gen Subj,2017,1861(7):1788-1800.
[31]GUO H,ZHANG X Y,PENG J,et al.RUVBL1,a novel C-RAF-binding protein,activates the RAF/MEK/ERK pathway to promote lung cancer tumorigenesis[J].Biochem Biophys Res Commun,2018,498(4):932-939.
[32]MIKESCH J H,HARTMANN W,ANGENENDT L,et al.AAA+ATPases reptin and pontin as potential diagnostic and prognostic biomarkers in salivary gland cancer-a short report[J].Cell Oncol(Dordr),2018,41(4):455-462.
[33]TANIUCHI K,FURIHATA M,IWASAKI S,et al.RUVBL1 directly binds actin filaments and induces formation of cell protrusions to promote pancreatic cancer cell invasion[J].Int J Oncol,2014,44(6):1945-1954.
[34]LAUSCHER J C,ELEZKURTAJ S,DULLAT S,et al.Increased pontin expression is a potential predictor for outcome in sporadic colorectal carcinoma[J].Oncol Rep,2012,28(5):1619-1624.