肝癌伴临床实验指标的变化特点及其与15个STR位点的关联
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摘要
目的：探讨肝癌主要临床实验指标的变化情况以及基因组中微卫星DNA与肝癌的关联。
方法：肝癌组是肝癌住院患者,共30例,男女各15例,年龄在37岁到81岁之间,平均年龄62.17岁。生化对照组是随机选取的健康体检者,年龄从40岁到80岁,平均年龄60.53,共30例。STR对照组是100位无肝癌的健康个体,年龄、性别、种族与肝癌组相匹配。以静脉血采血。用于肝功项目总蛋白(TP)、白蛋白(ALB)测定,生化项目甘油三脂(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、血糖(GLU)测定,肾功项目肌酐(CREA)、尿素(UREA)检测,免疫项目IgA、IgM、IgG检测,还有超敏CRP(h-CRP),以上项目检测均使用日立7600全自动生化分析仪。血常规项目WBC、Neu#、LY#、RBC、HGB、PLT检测,使用sysmex XE2000全自动分析仪。肿瘤标记物测定使用化学发光方法,包括AFP、CEA、CA153、NSE、CA50。STR采用PCR和五色荧光自动检测技术进行检测,STR包括D8S1179、D21S11、D7S820、CSF1PO、D3S1358、D5S818、D13S317、D16S539、D2S1338、D19S433、VWA、D12S391、D18S51、D6S1043、FGA。
结果：肝癌组肝功项目TP(g/L)、ALB(g/L)的平均值分别为69.11,38.92,对照组平均值分别为73.41,45.71,这两项均有显著性差异(P<0.05)。肾功项目肝癌组UREA(mmol/L)平均值为7.4,对照组为4.77,存在显著性差异(P<0.05), CREA (μmol/L)项目没有显著性差异。血常规项目中,肝癌组与对照组比较,RBC(1012/L)、HGB(g/L)、Neu# (109/L)、LY#(109/L)平均值分别为4.01、118.53、4.83、1.45,对照组平均值分别为4.47、129.90、3.09、2.12,这四项存在显著性差异(P<0.05),WBC(109/L)、PLT(109/L)无显著性差异(P>0.05)。在血糖、血脂项目检测中,肝癌组与对照组比较中,高密度胆固醇(HDLC, mmol/L)平均值为1.17,对照组平均值为1.62,有显著性差异(P<0.05)。血清葡萄糖(GLU, mmol/L)、甘油三酯(TG, mmol/L)、低密度胆固醇(LDLC, mmol/L)无显著性差异(P>0.05)。在超敏CRP(h-CRP)的检测中,肝癌组与正常对照组比较,超敏CRP有显著性差异(P<0.05)。免疫检测结果中,肝癌组与对照组比较,IgG(mg/L)有显著性差异(P<0.05)。肿瘤标记物检测结果中,肝癌组与对照组比较,AFP (ng/ml)、CEA (ng/ml)有显著性差异(P<0.05)。NSE(U/L)、CA15-3(U/L)、CA50(U/L)无显著性差异(P>0.05)。STR肝癌组中D8S1179-14、D19S433-14、D6S1043-20位点频数分别为0.300、0.450、0.117,对照组频数分别为0.170、0.270、0.030,这3项存在显着性差异(P<0.05)；其他项目没有显著性差异。
结论：肝癌患者伴有肝功、肾功、血常规、生化、肿瘤标志物、免疫系统不同程度的变化。STR肝癌组位点D6S1043-20、D19S433-14、D8S1179-14的频率高于对照组,其附近可能有肝癌的易感基因。
Objective:To assess the variation of main clinical indicators of Hepatocellular carcinoma (HCC) as well as changes in the genome of microsatellite DNA associated with Hepatocellular carcinoma (HCC).
Methods:A total of 30 Hepatocellular carcinoma (HCC) inpatients were included in the Hepatocellular carcinoma (HCC) group,15 males and 15 females, aged from 37 to 81 years old, the average age of 62.17 years. The biochemical control group recruited 30 healthy individuals, aged between 40 and 80 years old, the average age of 60.53 years,who were randomly selected from the physical examinees. The STR control group consisted of 100 healthy individuals without HCC,including 50 males and 50 females, which matched HCC group. Venous blood was collected for the detection of total protein (TP), albumin (ALB) to estimate the liver function,for the detection of triglyceride (TG), high density lipoprotein (HDL),low density lipoprotein (LDL) and glucose (GLU),for the detection of creatinine (CREA) and urea (UREA) for evaluating the renal function,for the detection of immunization items IgA, IgM, IgG, plus a super-sensitive CRP (h-CRP).All the above detections were carried out with the Hitachi 7600 Fully Automatic Biochemical Analyzer. The measure of WBC, Neu#, LY#, RBC, HGB, PLT was performed by the sysmex XE2000 automated analyzer. Tumor markers, included AFP, CEA, CA153, NSE, CA50,were conducted by means of chemiluminescence methods. And STR locis were carried with a polymerase chain reaction-restriction assay and the five-color fluorescence automatic detection technique,including D8S1179,D21 S1 1, D7S820,CSF1PO,D3S1358,D5S818,D13S317,D16S539,D2S1338,D19S433, VWA,D12S391,D18S51,D6S1043,FGA.
Results:The level of liver function items TP (g/L), ALB (g/L) on average in the Hepatocellular carcinoma (HCC) group were respectively 69.11 and 38.92,while in the control group they were respectively 73.41 and 45.71. There was a significant difference in the two items (P<0.05). Renal item UREA (mmol/L)in the Hepatocellular carcinoma (HCC) group averaged 7.4, while 4.77 in the control group. Again there was a significant difference in the test (P<0.05). However,the other test CREA (μmol/L) has no significant difference(P>0.05). The average values of blood components RBC、HGB、Neu# and LY# in the Hepatocellular carcinoma (HCC) group were respectively 4.01、118.53、4.83、1.45. while in the control group such average values were 4.47,129.90,3.09 and 2.12. There was a significant difference in these four items (P<0.05), while there was no significant difference in the other items. Comparing the HCC group with the control group,the level on average of blood glucose(GLU, mmol/L) and lipids:high density cholesterol (HDLC, mmol/L) was 1.17 versus 1.62, there was a significant difference in this item (P<0.05), but there was no significant difference in blood glucose(GLU, mmol/L), triglyceride (TG mmol/L) and low density cholesterol (LDLC, mmol/L) (P>0.05). In the ultra-sensitive CRP (h-CRP) test,the result of h-CRP had a significant difference (P>0.05). Comparing IgG(mg/L) in the Hepatocellular carcinoma (HCC) and in the control group(P<0.05),there was a significant difference, but in IgM(mg/L) and IgA(mg/L) items,there were no significant difference. The tumor marker AFP(ng/ml),CEA(ng/ml) in the Hepato-cellular carci-noma (HCC) and the control group had significant difference (P<0.05), there was no significant difference in the other markers.The loci frequencies of STR D8S1179-14,D19S433-14,D6S1043-20 in the Hepato-cellular carcinoma (HCC) group were respectively 0.300,0.450,0.117,and the same frequencies in the control group were respectively 0.170,0.270,0.030, there was significant difference in these three locis (P<0.05) while there was no significant difference in the other locis.
Conclusion:Changes in liver function, renal function, regular blood lipids,tumor markers and immune system occur to different degrees in the Hepatocellular carcinoma (HCC) patients. The loci frequencies of STRs D8S1179-14,D19S433-14,D6S1043-20 are higher than those in the control group, so there may be HCC susceptibility genes nearby.
方法：肝癌组是肝癌住院患者,共30例,男女各15例,年龄在37岁到81岁之间,平均年龄62.17岁。生化对照组是随机选取的健康体检者,年龄从40岁到80岁,平均年龄60.53,共30例。STR对照组是100位无肝癌的健康个体,年龄、性别、种族与肝癌组相匹配。以静脉血采血。用于肝功项目总蛋白(TP)、白蛋白(ALB)测定,生化项目甘油三脂(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、血糖(GLU)测定,肾功项目肌酐(CREA)、尿素(UREA)检测,免疫项目IgA、IgM、IgG检测,还有超敏CRP(h-CRP),以上项目检测均使用日立7600全自动生化分析仪。血常规项目WBC、Neu#、LY#、RBC、HGB、PLT检测,使用sysmex XE2000全自动分析仪。肿瘤标记物测定使用化学发光方法,包括AFP、CEA、CA153、NSE、CA50。STR采用PCR和五色荧光自动检测技术进行检测,STR包括D8S1179、D21S11、D7S820、CSF1PO、D3S1358、D5S818、D13S317、D16S539、D2S1338、D19S433、VWA、D12S391、D18S51、D6S1043、FGA。
结果：肝癌组肝功项目TP(g/L)、ALB(g/L)的平均值分别为69.11,38.92,对照组平均值分别为73.41,45.71,这两项均有显著性差异(P<0.05)。肾功项目肝癌组UREA(mmol/L)平均值为7.4,对照组为4.77,存在显著性差异(P<0.05), CREA (μmol/L)项目没有显著性差异。血常规项目中,肝癌组与对照组比较,RBC(1012/L)、HGB(g/L)、Neu# (109/L)、LY#(109/L)平均值分别为4.01、118.53、4.83、1.45,对照组平均值分别为4.47、129.90、3.09、2.12,这四项存在显著性差异(P<0.05),WBC(109/L)、PLT(109/L)无显著性差异(P>0.05)。在血糖、血脂项目检测中,肝癌组与对照组比较中,高密度胆固醇(HDLC, mmol/L)平均值为1.17,对照组平均值为1.62,有显著性差异(P<0.05)。血清葡萄糖(GLU, mmol/L)、甘油三酯(TG, mmol/L)、低密度胆固醇(LDLC, mmol/L)无显著性差异(P>0.05)。在超敏CRP(h-CRP)的检测中,肝癌组与正常对照组比较,超敏CRP有显著性差异(P<0.05)。免疫检测结果中,肝癌组与对照组比较,IgG(mg/L)有显著性差异(P<0.05)。肿瘤标记物检测结果中,肝癌组与对照组比较,AFP (ng/ml)、CEA (ng/ml)有显著性差异(P<0.05)。NSE(U/L)、CA15-3(U/L)、CA50(U/L)无显著性差异(P>0.05)。STR肝癌组中D8S1179-14、D19S433-14、D6S1043-20位点频数分别为0.300、0.450、0.117,对照组频数分别为0.170、0.270、0.030,这3项存在显着性差异(P<0.05)；其他项目没有显著性差异。
结论：肝癌患者伴有肝功、肾功、血常规、生化、肿瘤标志物、免疫系统不同程度的变化。STR肝癌组位点D6S1043-20、D19S433-14、D8S1179-14的频率高于对照组,其附近可能有肝癌的易感基因。
Objective:To assess the variation of main clinical indicators of Hepatocellular carcinoma (HCC) as well as changes in the genome of microsatellite DNA associated with Hepatocellular carcinoma (HCC).
Methods:A total of 30 Hepatocellular carcinoma (HCC) inpatients were included in the Hepatocellular carcinoma (HCC) group,15 males and 15 females, aged from 37 to 81 years old, the average age of 62.17 years. The biochemical control group recruited 30 healthy individuals, aged between 40 and 80 years old, the average age of 60.53 years,who were randomly selected from the physical examinees. The STR control group consisted of 100 healthy individuals without HCC,including 50 males and 50 females, which matched HCC group. Venous blood was collected for the detection of total protein (TP), albumin (ALB) to estimate the liver function,for the detection of triglyceride (TG), high density lipoprotein (HDL),low density lipoprotein (LDL) and glucose (GLU),for the detection of creatinine (CREA) and urea (UREA) for evaluating the renal function,for the detection of immunization items IgA, IgM, IgG, plus a super-sensitive CRP (h-CRP).All the above detections were carried out with the Hitachi 7600 Fully Automatic Biochemical Analyzer. The measure of WBC, Neu#, LY#, RBC, HGB, PLT was performed by the sysmex XE2000 automated analyzer. Tumor markers, included AFP, CEA, CA153, NSE, CA50,were conducted by means of chemiluminescence methods. And STR locis were carried with a polymerase chain reaction-restriction assay and the five-color fluorescence automatic detection technique,including D8S1179,D21 S1 1, D7S820,CSF1PO,D3S1358,D5S818,D13S317,D16S539,D2S1338,D19S433, VWA,D12S391,D18S51,D6S1043,FGA.
Results:The level of liver function items TP (g/L), ALB (g/L) on average in the Hepatocellular carcinoma (HCC) group were respectively 69.11 and 38.92,while in the control group they were respectively 73.41 and 45.71. There was a significant difference in the two items (P<0.05). Renal item UREA (mmol/L)in the Hepatocellular carcinoma (HCC) group averaged 7.4, while 4.77 in the control group. Again there was a significant difference in the test (P<0.05). However,the other test CREA (μmol/L) has no significant difference(P>0.05). The average values of blood components RBC、HGB、Neu# and LY# in the Hepatocellular carcinoma (HCC) group were respectively 4.01、118.53、4.83、1.45. while in the control group such average values were 4.47,129.90,3.09 and 2.12. There was a significant difference in these four items (P<0.05), while there was no significant difference in the other items. Comparing the HCC group with the control group,the level on average of blood glucose(GLU, mmol/L) and lipids:high density cholesterol (HDLC, mmol/L) was 1.17 versus 1.62, there was a significant difference in this item (P<0.05), but there was no significant difference in blood glucose(GLU, mmol/L), triglyceride (TG mmol/L) and low density cholesterol (LDLC, mmol/L) (P>0.05). In the ultra-sensitive CRP (h-CRP) test,the result of h-CRP had a significant difference (P>0.05). Comparing IgG(mg/L) in the Hepatocellular carcinoma (HCC) and in the control group(P<0.05),there was a significant difference, but in IgM(mg/L) and IgA(mg/L) items,there were no significant difference. The tumor marker AFP(ng/ml),CEA(ng/ml) in the Hepato-cellular carci-noma (HCC) and the control group had significant difference (P<0.05), there was no significant difference in the other markers.The loci frequencies of STR D8S1179-14,D19S433-14,D6S1043-20 in the Hepato-cellular carcinoma (HCC) group were respectively 0.300,0.450,0.117,and the same frequencies in the control group were respectively 0.170,0.270,0.030, there was significant difference in these three locis (P<0.05) while there was no significant difference in the other locis.
Conclusion:Changes in liver function, renal function, regular blood lipids,tumor markers and immune system occur to different degrees in the Hepatocellular carcinoma (HCC) patients. The loci frequencies of STRs D8S1179-14,D19S433-14,D6S1043-20 are higher than those in the control group, so there may be HCC susceptibility genes nearby.
引文
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50.杨连君,FHIT基因与肝癌的关系.诊断病理学杂志,2004,11(5)356-358.
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53.李君,代志军,李宗芳.雄激素受体基因中(CAG)n微卫星多态性与原发性肝癌.国际外科学杂志,2009,36(2)97-99.
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2. Wang Y,Kato N,Hoshida Y,et al.Interleukin-1 beta gene polymorphisms is associated with hepatocelluar carcinoma in hepatitis C virus infection. Hepatolo 2003,37(1):65-71.
3. Jeng Jen-Eing, Tsai Jung-Fa, Chuang Lee-Yea, Ho Mei-Shang, Lin Zu-Yau, Hsie. Min-Yuh, Chen Shin-Chern, Chuang Wan-Lung, Wang Liang-Yen, Yu Ming-Lung, Dai Chia-Yen, and Chang Jan-Gowth. Tumor Necrosis Factor-a 308.2 Polymor-phism Is Associated with Advanced Hepatic Fibrosis and Higher Risk for Hepatocellular Carcinoma.Neoplasia.2007,9(11):987-992.
4.4.P. Kummee, P. Tangkijvanich, Y. Poovorawan, N. Hirankarn. Association of HLA-DRB1*13 and TNF-α gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population. Journal of Viral Hepatitis,2007,14(12):841-848.
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6. Yue Wang, Naoya Kato, et al.UDP-Glucuronosyltransferase 1A7 Genetic Poly-morphisms Are Associated with Hepatocellular Carcinoma in Japanese Patients with Hepatitis C Virus Infection. Clin Cancer Res April 1,200410:2441-2446.
7. Ming-Whei Yu, Shi-Yi Yang, I-Jen Pan, Chih-Lin Lin, Chun-Jen Liu, Yun-Fan Liaw, Shi-Ming Lin, Pei-Jer Chen, Shou-Dong Lee, and Chien-Jen Chen. Poly-morphisms in XRCC1 and Glutathione S-Transferase Genes and Hepatitis B-Related Hepatocellular Carcinoma.J Natl Cancer Inst,2003; 95:1485-1488.
8. Gregory D. Kirk,Paul C. Turner, Yunyun Gong, Olufunmilayo A. Lesi, Maimuna Mendy, James J. Goedert, Andrew J. Hall, Hilton Whittle, Pierre Hainaut, Ruggero Montesano, and Christopher P. Wild. Hepatocellular Carcinoma and
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10. Brigitte Bressac, Michael Kew, Jack Wands, Mehmet Ozturk.Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa.Nature 1991.350(6317),429-431.
11.马威,张亮.人类短串联重复序列(STR)及其研究进展.大连医科大学学报,2007,29(1)78-81.
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1. Shariff MI, Cox IJ, Gomaa AI, Khan SA, Gedroyc W, Taylor-Robinson SD.Hepatocellular carcinoma:current trends in worldwide epidemiology, risk factors,diagnosis and therapeutics. Expert Rev Gastroenterol Hepatol.2009, 3(4):353-367.
2. Wang Y,Kato N,Hoshida Y,et al.Interleukin-1 beta gene polymorphisms is associated with hepatocelluar carcinoma in hepatitis C virus infection. Hepatolo 2003,37(1):65-71.
3. Jeng Jen-Eing, Tsai Jung-Fa, Chuang Lee-Yea, Ho Mei-Shang, Lin Zu-Yau, Hsie. Min-Yuh, Chen Shin-Chern, Chuang Wan-Lung, Wang Liang-Yen, Yu Ming-Lung, Dai Chia-Yen, and Chang Jan-Gowth. Tumor Necrosis Factor-a 308.2 Polymor-phism Is Associated with Advanced Hepatic Fibrosis and Higher Risk for Hepatocellular Carcinoma.Neoplasia.2007,9(11):987-992.
4.4.P. Kummee, P. Tangkijvanich, Y. Poovorawan, N. Hirankarn. Association of HLA-DRB1*13 and TNF-α gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population. Journal of Viral Hepatitis,2007,14(12):841-848.
5. Loredana Covolo, Umberto Gelatti, Renato Talamini, Seymour Garte, Paola Trevisi, Silvia Franceschi, Michela Franceschini, Fabio Barbone, Alessandro Tagger, Maria Lisa Ribero, Giovanni Parrinello, Valter Donadon, Giuseppe Nardi, Francesco Donato.Alcohol Dehydrogenase 3, Glutathione S-transferase M1 and Tl Polymorphisms, Alcohol Consumption and Hepatocellular Carcinoma (Italy). Cancer Causes Control,2005,16(7):831-838.
6. Yue Wang, Naoya Kato, et al.UDP-Glucuronosyltransferase 1A7 Genetic Poly-morphisms Are Associated with Hepatocellular Carcinoma in Japanese Patients with Hepatitis C Virus Infection. Clin Cancer Res April 1,200410:2441-2446.
7. Ming-Whei Yu, Shi-Yi Yang, I-Jen Pan, Chih-Lin Lin, Chun-Jen Liu, Yun-Fan Liaw, Shi-Ming Lin, Pei-Jer Chen, Shou-Dong Lee, and Chien-Jen Chen. Poly-morphisms in XRCC1 and Glutathione S-Transferase Genes and Hepatitis B-Related Hepatocellular Carcinoma.J Natl Cancer Inst,2003; 95:1485-1488.
8. Gregory D. Kirk,Paul C. Turner, Yunyun Gong, Olufunmilayo A. Lesi, Maimuna Mendy, James J. Goedert, Andrew J. Hall, Hilton Whittle, Pierre Hainaut, Ruggero Montesano, and Christopher P. Wild. Hepatocellular Carcinoma and
Polymorphisms in Carcinogen-Metabolizing and DNA Repair Enzymes in a Population with Aflatoxin Exposure and Hepatitis B Virus Endemicity. Cancer Epidemiol Biomarkers Prev February 200514:373-379.
9. Young Joon Yoon, Hye Young Chang, Sang Hoon Ahn, Ja Kyung Kim, Yong Kwang Park, Dae Ryong Kang, Jun Yong Park, Sung Min Myoung, Do Young Kim, Chae Yoon Chon, and Kwang-Hyub Han. MDM2 and p53 polymorphisms are associated with the development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Carcinogenesis.2008; 29:1192-1196.
10. Brigitte Bressac, Michael Kew, Jack Wands, Mehmet Ozturk.Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa.Nature 1991.350(6317),429-431.
11.马威,张亮.人类短串联重复序列(STR)及其研究进展.大连医科大学学报,2007,29(1)78-81.
12. Stocks T, Rapp K, Bj(?)rge T, Manjer J, Ulmer H, Selmer R, Lukanova A, Johansen D, Concin H, Tretli S, Hallmans G, Jonsson H, Stattin P. Blood glucose and risk of incident and fatal cancer in the metabolic syndrome and cancer project (me-can): analysis of six prospective cohorts. PLoS Med.2009,6(12):e1000201.
13. Obi N, Katabami T, Obi R, Odanaka M, Sasano K, Tanaka Y. Primary malignant hepatic glucagonoma:an autopsy case. Endocr J.2009.56(5):715-9.
14. Boldt, M.D., Parks, E.J.,2005. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest., 115(5):1343-1351.
15. Eisenberg, S., Levy, R.I.,1975. Lipoprotein metabolism. Adv. Lipid. Res., 13:1-89.
16. Welzel TM, Katki HA, Sakoda LC, Evans AA, London WT, Chen G, O'Broin S, Shen FM, Lin WY, McGIynn KA. Blood folate levels and risk of liver damage and hepatocellular carcinoma in a prospective high-risk cohort. Cancer Epidemiol Biomarkers Prev.2007,16(6):1279-1282.
17. Krause T, Hauenstein K, Studier-Fischer B, Schuemichen C, Moser E. Improved evaluation of technetium-99m-red blood cell SPECT in hemangioma of the liver. JNucI Med.1993,34(3):375-380.
18. Tan HT, Low J, Lim SG, Chung MC. Serum autoantibodies as biomarkers for early cancer detection. FEBS J.2009,276(23):6880-904.
19. Peng XQ, Wang F, Geng X, Zhang WM. Current advances in tumor proteomics and candidate biomarkers for hepatic cancer. Expert Rev Proteomics.2009, 6(5):551-61.
20. Chan SL, Chan AT, Yeo W. Role of alpha-fetoprotein in hepatocellular carcinoma: prognostication, treatment monitoring or both? Future Oncol.2009,5(6):889-899.
21. Yan BC, Hart JA. Recent developments in liver pathology. Arch Pathol Lab Med. 2009 Jul;133(7):1078-1086.
22. Phillips, G.B.,1960. The lipid composition of serum in patients with liver disease. J. Clin. Invest.,39:1639-1650.