肝细胞癌患者外周血PD-L1基因多态性与肝细胞癌易感性及预后关系研究
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摘要
目的探讨肝细胞癌(HCC)患者血程序性死亡配体(PD-L)1基因多态性与易感性和预后之间的关系。方法 2010年1月～2015年6月诊治的HCC患者100例和肝功能正常的正常人100例,采集外周血,采用直接测序法和聚合酶链反应-单链构象多态性分析(PCR-SSCP)法检测PD-L1基因rs4143185、rs17718883和rs28906583三个位点的单核苷酸多态性(SNP),分析其与肝细胞癌易感性和预后之间的关系。结果携带rs2890658的AC杂合突变基因可以降低肝细胞癌的发病风险(OR=0.391,P<0.05),携带rs17718883的CG杂合突变基因也会降低肝细胞癌的发病风险(OR=0.009,P<0.05);rs2890658位点的3个基因型AA、AC和CC的中位生存时间分别为18(15,21)m、20(16,22)m和19(15,21)m,组间差异无统计学意义(P>0.05),合并AC和CC基因型者,中位生存时间为20(16,23)m,明显比AA基因型者长,差异有统计学意义(P<0.05);携带rs4143185位点的3个基因型CC、GC和GC者中位生存时间分别为16(13,19)m、20(15,23)m和17(15,21)m,组间差异有统计学意义(P<0.05),合并CG+GG者中位生存时间为21(17,24)m,明显长于CC者,差异有统计学意义(P<0.05);COX回归分析显示,携带rs4143185突变基因者可以获得较好的预后(HR<1,P<0.05)。结论检测外周血PD-L1基因多态性可能有助于筛选HCC高危人群中的高危人群,并可能对预测患者预后有帮助。
O bjective To investigate the polymorphism of programmed death-ligand 1(PD-L1) gene in susceptibility and prognosis of patients with hepatocellular carcinoma(HCC). Methods 100 patients with HCC and 100 healthy persons were recruited in our hospital between January 2010 and June 2015. The peripheral blood were collected to assay the single nucleotide polymorphisms(SNP),including rs4143185,rs17718883 and rs28906583,of PD-L1 gene by direct sequencing and polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP). R esults The AC heterozygous mutation gene of rs2890658 reduced the risk of liver cancer susceptibility(OR=0.391,P<0.05),and the CG heterozygous mutation of rs17718883 also reduced the risk of liver cancer susceptibility(OR=0.009,P<0.05);the median survival times of 3 genotypes(AA,AC and CC) of rs2890658 were 18(15,21) m,20(16,22) m and 19(15,21) m,no significant differences among(P>0.05);the median survival time in combination of genotype AC and CC was 20(16,23) m,much longer than carrying genotype AA(P<0.05);there were significantly differences among survival times in individuals carrying CC,GC and GC of rs4143185 gene [16(13,19) m,20(15,23) m and 17(15,21) m,respectively,P<0.05],and the survival time in persons carrying combination of CG and GG was 21(17,24) m,much longer than those carrying CC(P<0.05);COX regression analysis showed that patients carrying mutant genes of rs4143185 had a good prognosis(HR <1,P <0.05). C onclusion The detection of blood PD-L1 gene polymorphism might be useful in clinical practice in screening individuals with high risk of HCC susceptibility and in forecasting the prognosis of patients with HCC.
O bjective To investigate the polymorphism of programmed death-ligand 1(PD-L1) gene in susceptibility and prognosis of patients with hepatocellular carcinoma(HCC). Methods 100 patients with HCC and 100 healthy persons were recruited in our hospital between January 2010 and June 2015. The peripheral blood were collected to assay the single nucleotide polymorphisms(SNP),including rs4143185,rs17718883 and rs28906583,of PD-L1 gene by direct sequencing and polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP). R esults The AC heterozygous mutation gene of rs2890658 reduced the risk of liver cancer susceptibility(OR=0.391,P<0.05),and the CG heterozygous mutation of rs17718883 also reduced the risk of liver cancer susceptibility(OR=0.009,P<0.05);the median survival times of 3 genotypes(AA,AC and CC) of rs2890658 were 18(15,21) m,20(16,22) m and 19(15,21) m,no significant differences among(P>0.05);the median survival time in combination of genotype AC and CC was 20(16,23) m,much longer than carrying genotype AA(P<0.05);there were significantly differences among survival times in individuals carrying CC,GC and GC of rs4143185 gene [16(13,19) m,20(15,23) m and 17(15,21) m,respectively,P<0.05],and the survival time in persons carrying combination of CG and GG was 21(17,24) m,much longer than those carrying CC(P<0.05);COX regression analysis showed that patients carrying mutant genes of rs4143185 had a good prognosis(HR <1,P <0.05). C onclusion The detection of blood PD-L1 gene polymorphism might be useful in clinical practice in screening individuals with high risk of HCC susceptibility and in forecasting the prognosis of patients with HCC.
引文
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[15]Wang W,Ping L,He Y.A gene polymorphism in PD-L1promoter region is not associated with PD-L1 expression and patients’survival in gastric cancer.Cancer Immunol Immunother,2017,32(3):1-3.
[16]Lee SY,Jung DK,Jin EC,et al.PD-L1 polymorphism can predict clinical outcomes of non-small cell lung cancer patients treated with first-line paclitaxel-cisplatin chemotherapy.Sci Rep,2016,6(4):125-125.
[17]Mojtahedi Z,Mohmedi M,Rahimifar S,et al.Programmed death-1 gene polymorphism(PD-1.5 C/T)is associated with colon cancer.Gene,2012,508(2):229-237.
[18]程仕光,李清,彭宇,等.PD-L1基因多态性与肝细胞癌易感性以及预后之间的关系.第三军医大学学报,2017,39(5):487-492.
[19]Wang W,Li F,Mao Y,et al.A mi R-570 binding site polymorphism in the B7-H1 gene is associated with the risk of gastric adenocarcinoma.Hum Genet,2013,132(6):641-648.
[20]Zhou RM,Li Y,Liu JH,et al.Programmed death-1 lignd-1gene rs2890658 polymorphism associated with the risk of esophageal squamous cell carcinoma in smokers.Cancer Biomark,2017:1-7.
[21]Mu CY,Huang JA,Chen Y,et al.High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation.Med Oncol,2011,28(3):682-688.
[2]Borzio M,Fornari F,De SI,et al.Adherence to American Association for the Study of Liver Diseases guidelines for the management of hepatocellular carcinoma:results of an Italian field practice multicenter study.Fut Oncol,2013,9(2):283-294.
[3]Gavriilidis P,Askari A,Azoulay D.Survival following redo hepatectomy vs radiofrequency ablation for recurrent hepatocellular carcinoma:a systematic review and meta-analysis.HPB(Oxford),2017,19(1):3-9.
[4]Altekruse SF,Mcglynn KA,Reichman ME.Hepatocellular carcinoma incidence,mortality,and survival trends in the United States from 1975 to 2005.J Clin Oncol,2009,27(9):1485-1491.
[5]Groeger S,Howaldt HP,Raifer H,et al.Oral squamous carcinoma cells express B7-H1 and B7-DC receptors in vivo.Pathol Oncol Res,2017,23(1):1-12.
[6]Dinesh RK,Hahn BH,Singh RP.PD-1,gender,and autoimmunity.Autoimmun Rev,2010,9(8):583-587.
[7]曹霖霖,张国梁.慢性乙型肝炎患者PD-1/PD-L1信号通路的免疫调节作用研究进展.实用肝脏病杂志,2015,18(6):682-686.
[8]Desantis CE,Lin CC,Mariotto AB,et al.Cancer treatment and survivorship statistics,2014.CA Cancer J Clin,2012,62(4):252-271.
[9]Kettenbach J,Stadler A,Katzler IV,et al.Drug-loaded microspheres for the treatment of liver cancer:review of current results.Cardiovasc Intervent Radiol,2008,31(3):468-476.
[10]Le BS,Champiat S,Routier E,et al.Onset of connective tissue disease following anti-PD1/PD-L1 cancer immunotherapy.Ann Rheum Dis,2017(12)3:1-9
[11]Mletzko S,Pinato DJ,Robey RC,et al.Programmed death ligand 1(PD-L1)expression influences the immune-tolerogenic microenvironment in antiretroviral therapy-refractory Kaposi's sarcoma:A pilot study.Oncoimmunology,2017,6(8):e1304337.
[12]Blank C,Mackensen A.Contribution of the PD-L1/PD-1pathway to T-cell exhaustion:an update on implications for chronic infections and tumor evasion.Cancer Immunol Immunother,2007,56(5):739-745.
[13]万和荷,刘丽丽,侯勇,等.PD-1/PD-L1信号通路与慢性乙型肝炎.实用肝脏病杂志,2014,17(6):661-664.
[14]Teng MW,Ngiow SF,Ribas A,et al.Classifying cancers based on T-cell infiltration and PD-L1.Cancer Res,2015,75(11):2139-2145.
[15]Wang W,Ping L,He Y.A gene polymorphism in PD-L1promoter region is not associated with PD-L1 expression and patients’survival in gastric cancer.Cancer Immunol Immunother,2017,32(3):1-3.
[16]Lee SY,Jung DK,Jin EC,et al.PD-L1 polymorphism can predict clinical outcomes of non-small cell lung cancer patients treated with first-line paclitaxel-cisplatin chemotherapy.Sci Rep,2016,6(4):125-125.
[17]Mojtahedi Z,Mohmedi M,Rahimifar S,et al.Programmed death-1 gene polymorphism(PD-1.5 C/T)is associated with colon cancer.Gene,2012,508(2):229-237.
[18]程仕光,李清,彭宇,等.PD-L1基因多态性与肝细胞癌易感性以及预后之间的关系.第三军医大学学报,2017,39(5):487-492.
[19]Wang W,Li F,Mao Y,et al.A mi R-570 binding site polymorphism in the B7-H1 gene is associated with the risk of gastric adenocarcinoma.Hum Genet,2013,132(6):641-648.
[20]Zhou RM,Li Y,Liu JH,et al.Programmed death-1 lignd-1gene rs2890658 polymorphism associated with the risk of esophageal squamous cell carcinoma in smokers.Cancer Biomark,2017:1-7.
[21]Mu CY,Huang JA,Chen Y,et al.High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation.Med Oncol,2011,28(3):682-688.