胰腺导管腺癌基因拷贝数改变的研究
|
摘要
【背景与目的】基因组DNA的非随机改变在胰腺导管腺癌(PDAC)的发生发展中起重要的作用,既往研究多局限于以细胞系为研究对象,利用BAC探针的array CGH鉴定基因组DNA非随机改变。本研究通过寡核苷酸array CGH分析胰腺导管腺癌新鲜组织标本,寻找胰腺导管腺癌特异的DNA改变,筛选出可能与胰腺导管腺癌发生发展密切相关的DNA拷贝数改变和相应的基因。
【材料与方法】收集2007年6月至2008年12月PDAC患者手术切除肿瘤组织标本15例,利用显微切割技术,富集肿瘤细胞,提取基因组DNA,通过array CGH分析,鉴定PDAC的基因拷贝数改变。应用荧光原位杂交(FISH)和实时定量PCR方法验证array CGH的结果。收集1999年～2008年间手术切除的PDAC65例,慢性胰腺炎8例,构建组织芯片,应用免疫组织化学(IHC)方法检测在array CGH中鉴定出的扩增基因PSCA和HMGA2的表达情况,分析其与PDAC临床病理参数的关系。
【结果】Array CGH结果中,有11个增益频率在80%以上的染色体区段,分别为:1q31.3、3p22.1、3p22.31、3p22.3、8q24.3、10q11.23、14q12、16p13.3、17q24.1、Xp11.21和Xq28,其中包括畸变频率＞20%的高拷贝扩增基因80个。发现5个缺失频率≥80%的染色体区段,分别为:5p13.3、12q13.13、17p13.1、17q21.31、Xq11.1,其中包含畸变频率＞20%的缺失基因144个。Array CGH、FISH和q-PCR实验均表明8q24.3的PSCA基因扩增。IHC结果提示:PSCA和HMGA2在PDAC中的阳性表达率分别为67.2%和76.7%。PSCA和HMGA2的表达与患者年龄、性别、T分期、M分期、分化程度及预后无相关性,但均与淋巴结转移相关(PSCA:x~2=4.370,P=0.037;HMGA2:x~2=13.062,P=0.001)。
【结论】PDAC基因拷贝数改变频率高、位点多,PSCA和HMGA2扩增和过表达可能作为PDAC淋巴结转移的分子标志。
【Background and Purpose】DNA copy number alterations play an important role in the initiation and progression of pancreatic ductal adenocarcinoma(PDAC).There have been some reports on DNA changes of PDAC detected by BAC-based array comparative genomic hybridization(array CGH),but most of them were performed on pancreatic cancer cell lines.In the present study,we used oligonucleotide array CGH to identify genetic alterations of PDAC genome.
【Patients and Methods】The tissue samples were obtained from 15 PDAC.Tumor cells collected by microdissection and genomic DNA were isolated.Array CGH was performed with the Agilent Human Genome CGH 44B array.DNA copy number alterations of PDAC were validated by fluorescence in situ hybridization(FISH) and real-time PCR.Tissue microarray was constructed,containing 65 PDAC and 8 chronic pancreatitis tissues.The expression of PSCA and HMGA2 proteins were detected by using immunohistochemical method and the relationships between the proteins expression and clinicopathological parameters of PDAC were analyzed.
【Results】Profiles of 15 PDAC identified multiple chromosomal regions with DNA copy number alterations.Loci with(＞80%cases) gains were at 1q31.3,3p22.1,3p22.31, 3p22.3,8q24.3,10q11.23,14q12,16p13.3,17q24.1,Xp11.21,and Xq28.Eighty genes were amplified in≥4 out of 15 cases(＞20%).The most frequent losses(＞80%) were at 5p13.3,12q13.13,17p13.1,17q21.31,and Xq11.1.One hundred and forty-four loci with deletions were detected(＞20.0%).Q-PCR and FISH results confirmed that the PSCA gene was of amplification.IHC analysis showed that PSCA and HMGA2 expressed in 67.2%and 76.7%of tumors,respectively.The positive expression of PSCA and HMGA2 was associated with lymph node metastases(PSCA:x~2=4.370,P=0.037;HMGA2:x~2= 13.062,P=0.001).
【Conclusions】There existed lots of chromosomal loci with frequent alterations of DNA copy number in PDAC.PSCA and HMGA2 might be two useful biomarkers in more advanced stage of PDAC.
【材料与方法】收集2007年6月至2008年12月PDAC患者手术切除肿瘤组织标本15例,利用显微切割技术,富集肿瘤细胞,提取基因组DNA,通过array CGH分析,鉴定PDAC的基因拷贝数改变。应用荧光原位杂交(FISH)和实时定量PCR方法验证array CGH的结果。收集1999年～2008年间手术切除的PDAC65例,慢性胰腺炎8例,构建组织芯片,应用免疫组织化学(IHC)方法检测在array CGH中鉴定出的扩增基因PSCA和HMGA2的表达情况,分析其与PDAC临床病理参数的关系。
【结果】Array CGH结果中,有11个增益频率在80%以上的染色体区段,分别为:1q31.3、3p22.1、3p22.31、3p22.3、8q24.3、10q11.23、14q12、16p13.3、17q24.1、Xp11.21和Xq28,其中包括畸变频率＞20%的高拷贝扩增基因80个。发现5个缺失频率≥80%的染色体区段,分别为:5p13.3、12q13.13、17p13.1、17q21.31、Xq11.1,其中包含畸变频率＞20%的缺失基因144个。Array CGH、FISH和q-PCR实验均表明8q24.3的PSCA基因扩增。IHC结果提示:PSCA和HMGA2在PDAC中的阳性表达率分别为67.2%和76.7%。PSCA和HMGA2的表达与患者年龄、性别、T分期、M分期、分化程度及预后无相关性,但均与淋巴结转移相关(PSCA:x~2=4.370,P=0.037;HMGA2:x~2=13.062,P=0.001)。
【结论】PDAC基因拷贝数改变频率高、位点多,PSCA和HMGA2扩增和过表达可能作为PDAC淋巴结转移的分子标志。
【Background and Purpose】DNA copy number alterations play an important role in the initiation and progression of pancreatic ductal adenocarcinoma(PDAC).There have been some reports on DNA changes of PDAC detected by BAC-based array comparative genomic hybridization(array CGH),but most of them were performed on pancreatic cancer cell lines.In the present study,we used oligonucleotide array CGH to identify genetic alterations of PDAC genome.
【Patients and Methods】The tissue samples were obtained from 15 PDAC.Tumor cells collected by microdissection and genomic DNA were isolated.Array CGH was performed with the Agilent Human Genome CGH 44B array.DNA copy number alterations of PDAC were validated by fluorescence in situ hybridization(FISH) and real-time PCR.Tissue microarray was constructed,containing 65 PDAC and 8 chronic pancreatitis tissues.The expression of PSCA and HMGA2 proteins were detected by using immunohistochemical method and the relationships between the proteins expression and clinicopathological parameters of PDAC were analyzed.
【Results】Profiles of 15 PDAC identified multiple chromosomal regions with DNA copy number alterations.Loci with(＞80%cases) gains were at 1q31.3,3p22.1,3p22.31, 3p22.3,8q24.3,10q11.23,14q12,16p13.3,17q24.1,Xp11.21,and Xq28.Eighty genes were amplified in≥4 out of 15 cases(＞20%).The most frequent losses(＞80%) were at 5p13.3,12q13.13,17p13.1,17q21.31,and Xq11.1.One hundred and forty-four loci with deletions were detected(＞20.0%).Q-PCR and FISH results confirmed that the PSCA gene was of amplification.IHC analysis showed that PSCA and HMGA2 expressed in 67.2%and 76.7%of tumors,respectively.The positive expression of PSCA and HMGA2 was associated with lymph node metastases(PSCA:x~2=4.370,P=0.037;HMGA2:x~2= 13.062,P=0.001).
【Conclusions】There existed lots of chromosomal loci with frequent alterations of DNA copy number in PDAC.PSCA and HMGA2 might be two useful biomarkers in more advanced stage of PDAC.
引文
1.Jemal A,Siegel R,Ward E,et al.Cancer statistics,2008.CA:a cancer journal for clinicians 2008;58(2):71-96.
2.张思维,陈万青,孔灵芝,等。.中国部分市县1998～2002年恶性肿瘤的发病与死亡.中国肿瘤2006;15(7):430-48.
3.Maitra A,Adsay NV,Argani P,et al.Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray.Mod Pathol 2003;16(9):902-12.
4.Harada T,Okita K,Shiraishi K,et al.Detection of genetic alterations in pancreatic cancers by comparative genomic hybridization coupled with tissue microdissection and degenerate oligonucleotide primed polymerase chain reaction.Oncology 2002;62(3):251-8.
5.Gorunova L,Hoglund M,Andren-Sandberg A,et al.Cytogenetic analysis of pancreatic carcinomas:intratumor heterogeneity and nonrandom pattern of chromosome aberrations.Genes,chromosomes & cancer 1998;23(2):81-99.
6.Harada T,Baril P,Gangeswaran R,et al.Identification of genetic alterations in pancreatic cancer by the combined use of tissue microdissection and array-based comparative genomic hybridisation.British journal of cancer 2007;96(2):373-82.
7.Harada T,Chelala C,Bhakta V,et al.Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays.Oncogene 2008;27(13):1951-60.
8.Harada T,Chelala C,Crnogorac-Jurcevic T,Lemoine NR.Genome-wide analysis of pancreatic cancer using microarray-based techniques.Pancreatology 2009;9(1-2):13-24.
9.Fritz S,Fernandez-del Castillo C,Mino-Kenudson M,et al.Global genomic analysis of intraductal papillary mucinous neoplasms of the pancreas reveals significant molecular differences compared to ductal adenocarcinoma.Annals of surgery 2009;249(3):440-7.
10.Ostroverkhova NV,Nazarenko SA,Cheremnykh AD.[Comparative genomic hybridization as a new method for detection of genomic imbalance].Genetika 2002;38(2):149-60.
11.Lockwood WW,Chari R,Chi B,Lam WL.Recent advances in array comparative genomic hybridization technologies and their applications in human genetics.Eur J Hum Genet 2006;14(2):139-48.
12.Kallioniemi A.CGH microarrays and cancer.Current opinion in biotechnology 2008;19(1):36-40.
13.Davies JJ,Wilson IM,Lam WL.Array CGH technologies and their applications to cancer genomes.Chromosome Res 2005;13(3):237-48.
14.Pinkel D,Albertson DG.Comparative genomic hybridization.Annual review of genomics and human genetics 2005;6:331-54.
15.Shinawi M,Cheung SW.The array CGH and its clinical applications.Drug discovery today 2008;13(17-18):760-70.
16.Pfister S,Remke M,Benner A,et al.Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci.J Clin Oncol 2009;27(10):1627-36.
17.Strefford JC,Parker H.Array-based comparative genomic hybridization as a tool for analyzing the leukemia genome.Methods in molecular biology(Clifton,NJ 2009;538:151-77.
18.Santos SC,Cavalli IJ,Ribeiro EM,et al.Patterns of DNA copy number changes in sentinel lymph node breast cancer metastases.Cytogenetic and genome research 2008;122(1):16-21.
19.Huang J,Pang J,Watanabe T,Ng HK,Ohgaki H.Whole genome amplification for array comparative genomic hybridization using DNA extracted from formalin-fixed,paraffin-embedded histological sections.J Mol Diagn 2009;11(2):109-16.
20.Bauer VL,Braselmann H,Henke M,et al.Chromosomal changes characterize head and neck cancer with poor prognosis.Journal of molecular medicine(Berlin,Germany) 2008;86(12):1353-65.
21.Nowak NJ,Gaile D,Conroy JM,et al.Genome-wide aberrations in pancreatic adenocarcinoma.Cancer genetics and cytogenetics 2005;161(l):36-50.
22.Heidenblad M,Schoenmakers EF,Jonson T,et al.Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines.Cancer research 2004;64(9):3052-9.
23.Bashyam MD,Bair R,Kim YH,et al.Array-based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer.Neoplasia(New York,NY 2005;7(6):556-62.
24.Gysin S,Rickert P,Kastury K,McMahon M.Analysis of genomic DNA alterations and mRNA expression patterns in a panel of human pancreatic cancer cell lines.Genes,chromosomes & cancer 2005;44(1):37-51.
25.Loukopoulos P,Shibata T,Katoh H,et al.Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinoma:identification of genetic indicators that predict patient outcome.Cancer science 2007;98(3):392-400.
26.Silasi DA,Alvero AB,Mor J,et al.Detection of cancer-related proteins in fresh-frozen ovarian cancer samples using laser capture microdissection.Methods in molecular biology(Clifton,NJ 2008;414:35-45.
27.Hergenhahn M,Kenzelmann M,Grone HJ.Laser-controlled microdissection of tissues opens a window of new opportunities.Pathology,research and practice 2003;199(6):419-23.
28.Fuller AP,Palmer-Toy D,Erlander MG,Sgroi DC.Laser capture microdissection and advanced molecular analysis of human breast cancer.Journal of mammary gland biology and neoplasia 2003;8(3):335-45.
29.Bilimoria KY,Bentrem DJ,Ko CY,et al.Validation of the 6th edition AJCC Pancreatic Cancer Staging System:report from the National Cancer Database.Cancer 2007;110(4):738-44.
30.Niederhuber JE,Brennan MF,Menck HR.The National Cancer Data Base report on pancreatic cancer.Cancer 1995;76(9):1671-7.
31.沈魁 马刚,郭克见．胰腺癌诊断与外科治疗现状1008例调查分析．中华外科杂志 1998；36(12)：766-9．
32.Hidalgo M,Castellano D,Paz-Ares L,et al.Phase Ⅰ-Ⅱ study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.J Clin Oncol 1999;17(2):585-92.
33.Crino L,Mosconi AM,Calandri C,et al.Gemcitabine in advanced pancreatic cancer:a phase II trial.Am J Clin Oncol 2001;24(3):296-8.
34.Heinemann V.Gemcitabine:progress in the treatment of pancreatic cancer.Oncology 2001;60(1):8-18.
35.Eckel F,Schmelz R,Erdmann J,Mayr M,Lersch C.Phase Ⅱ trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma.Cancer Invest 2003;21(5):690-4.
36.Kleespies A,Jauch KW,Bruns CJ.Tyrosine kinase inhibitors and gemcitabine:new treatment options in pancreatic cancer? Drug Resist Updat 2006;9(1-2):1-18.
37.Saif MW,Karapanagiotou L,Syrigos K.Genetic alterations in pancreatic cancer.World J Gastroenterol 2007;13(33):4423-30.
38.Moore MJ,Goldstein D,Hamm J,et al.Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer:a phase Ⅲ trial of the National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol 2007;25(15):1960-6.
39.Jong K,Marchiori E,Meijer G,Vaart AV,Ylstra B.Breakpoint identification and smoothing of array comparative genomic hybridization data.Bioinformatics(Oxford,England) 2004;20(18):3636-7.
40.Chari R,Lockwood WW,Lam WL.Computational Methods for the Analysis of Array Comparative Genomic Hybridization.Cancer informatics 2006;2:48-58.
41.Boehm JS,Zhao JJ,Yao J,et al.Integrative genomic approaches identify IKBKE as a breast cancer oncogene.Cell 2007;129(6):1065-79.
42.Agami R.All roads lead to IKKepsilon.Cell 2007;129(6):1043-5.
43.Reiter RE,Gu Z,Watabe T,et al.Prostate stem cell antigen:a cell surface marker overexpressed in prostate cancer.Proceedings of the National Academy of Sciences of the United States of America 1998;95(4):1735-40.
44.郎根强 孙盈浩．前列腺干细胞抗原与前列腺癌．国外医学泌尿系统分册2002；22(5)：280-2．
45.Sardana G,Do well B,Diamandis EP.Emerging bio markers for the diagnosis and prognosis of prostate cancer.Clinical chemistry 2008;54(12):1951-60.
46.Panteleakou Z,Lembessis P,Sourla A,et al.Detection of circulating tumor cells in prostate cancer patients:methodological pitfalls and clinical relevance.Molecular medicine(Cambridge,Mass 2009;15(3-4):101-14.
47.Argani P,Rosty C,Reiter RE,et al.Discovery of new markers of cancer through serial analysis of gene expression:prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma.Cancer research 2001;61(11):4320-4.
48.Cao D,Maitra A,Saavedra JA,Klimstra DS,Adsay NV,Hruban RH.Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms:additional evidence of different genetic pathways.Mod Pathol 2005;18(6):752-61.
49.Wente MN,Jain A,Kono E,et al.Prostate stem cell antigen is a putative target for immunotherapy in pancreatic cancer.Pancreas 2005;31(2):119-25.
50.McCarthy DM,Maitra A,Argani P,et al.Novel markers of pancreatic adenocarcinoma in fine-needle aspiration:mesothelin and prostate stem cell antigen labeling increases accuracy in cytologically borderline cases.Appl Immunohistochem Mol Morphol 2003;11(3):238-43.
51.Yong KT,Ding H,Roy I,et al.Imaging pancreatic cancer using bioconjugated InP quantum dots.ACS nano 2009;3(3):502-10.
52.Tanaka M,Komatsu N,Terakawa N,et al.Increased levels of IgG antibodies against peptides of the prostate stem cell antigen in the plasma of pancreatic cancer patients.Oncology reports 2007;18(1):161-6.
53.Foss CA,Fox JJ,Feldmann G,et al.Radiolabeled anti-claudin 4 and anti-prostate stem cell antigen:initial imaging in experimental models of pancreatic cancer.Mol Imaging 2007;6(2):131-9.
54.Rodriguez JA,Li M,Yao Q,Chen C,Fisher WE.Gene overexpression in pancreatic adenocarcinoma:diagnostic and therapeutic implications.World journal of surgery 2005;29(3):297-305.
55.Gu Z,Yamashiro J,Kono E,Reiter RE.Anti-prostate stem cell antigen monoclonal antibody 1G8 induces cell death in vitro and inhibits tumor growth in vivo via a Fc-independent mechanism.Cancer research 2005;65(20):9495-500.
56.Adsay NV,Basturk O,Cheng JD,Andea AA.Ductal neoplasia of the pancreas:nosologic,clinicopathologic,and biologic aspects.Seminars in radiation oncology 2005;15(4):254-64.
57.杨文彬 蔡锋,程传涛,曹罡,秦兆寅.人胰腺癌中前列腺干细胞抗原及紧密连接蛋白-4的表达.中国医学科学院学报2008;30(6):728-31.
58.Bustin M,Reeves R.High-mobility-group chromosomal proteins:architectural components that facilitate chromatin function.Progress in nucleic acid research and molecular biology 1996;54:35-100.
59.Motoyama K,Inoue H,Nakamura Y,Uetake H,Sugihara K,Mori M.Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family.Clin Cancer Res 2008;14(8):2334-40.
60.Hristov AC,Cope L,Reyes MD,et al.HMGA2 protein expression correlates with lymph node metastasis and increased tumor grade in pancreatic ductal adenocarcinoma.Mod Pathol 2009;22(1):43-9.
61.Abe N,Watanabe T,Suzuki Y,et al.An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue.British journal of cancer 2003;89(11):2104-9.
1.Jemal A,Siegel R,Ward E,et aI.Cancer statistics,2008.CA Cancer J Clin 2008;58(2):71-96.
2.张思维,陈万青,孔灵芝,等。中国部分市县1998～2002年恶性肿瘤的发病与死亡.中国肿瘤2006;15(7):430-48.
3.Katz MH,Hwang R,Fleming JB,Evans DB.Tumor-node-metastasis staging of pancreatic adenocarcinoma.CA:a cancer journal for clinicians 2008;58(2):111-25.
4.Bilimoria KY,Bentrem D J,Ko CY,et al.Validation of the 6th edition AJCC Pancreatic Cancer Staging System:report from the National Cancer Database.Cancer 2007;110(4):738-44.
5.Niederhuber JE,Brennan MF,Menck HR.The National Cancer Data Base report on pancreatic cancer.Cancer 1995;76(9):1671-7.
6.沈魁 马刚,郭克见.胰腺癌诊断与外科治疗现状1008例调查分析.中华外科杂志1998;36(12):766-9.
7.Richter A,Niedergethmann M,Sturm JW,Lorenz D,Post S,Trede M.Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head:25-year experience.World J Surg 2003;27(3):324-9.
8.Carpelan-Holmstrom M,Nordling S,Pukkala E,et al.Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry.Gut 2005;54(3):385-7.
9.Wagner M,Redaelli C,Lietz M,Seiler CA,Friess H,Buchler MW.Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma.Br J Surg 2004;91(5):586-94.
10.Ozkan H,Kaya M,Cengiz A.Comparison of tumor marker CA 242 with CA 19-9and carcinoembryonic antigen(CEA) in pancreatic cancer.Hepato-gastroenterology 2003;50(53):1669-74.
11.Grote T,Logsdon CD.Progress on molecular markers of pancreatic cancer.Curr Opin Gastroenterol 2007;23(5):508-14.
12.Goonetilleke KS,Siriwardena AK.Systematic review of carbohydrate antigen(CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer.Eur J Surg Oncol 2007;33(3):266-70.
13.Fry LC,Monkemuller K,Malfertheiner P.Molecular markers of pancreatic cancer:development and clinical relevance.Langenbecks Arch Surg 2008;393(6):883-90.
14.Goggins M.Molecular markers of early pancreatic cancer.J Clin Oncol 2005;23(20):4524-31.
15.Boeck S,Stieber P,Holdenrieder S,Wilkowski R,Heinemann V.Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer.Oncology 2006;70(4):255-64.
16.Locker GY,Hamilton S,Harris J,et al.ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer.J Clin Oncol 2006;24(33):5313-27.
17.Chang CY,Huang SP,Chiu HM,Lee YC,Chen MF,Lin JT.Low efficacy of serum levels of CA 19-9 in prediction of malignant diseases in asymptomatic population in Taiwan.Hepatogastroenterology 2006;53(67):l-4.
18.Ziske C,Schlie C,Gorschluter M,et al.Prognostic value of CA 19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine.Br J Cancer 2003;89(8):1413-7.
19.Ferrone CR,Finkelstein DM,Thayer SP,Muzikansky A,Fernandez-delCastillo C,Warshaw AL.Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma.J Clin Oncol 2006;24(18):2897-902.
20.Kilic M,Gocmen E,Tez M,Ertan T,Keskek M,Koc M.Value of preoperative serum CA 19-9 levels in predicting resectability for pancreatic cancer.Can J Surg 2006;49(4):241-4.
21.Liang JJ,Kimchi ET,Staveley-O'Carroll KF,Tan D.Diagnostic and prognostic biomarkers in pancreatic carcinoma.Int J Clin Exp Pathol 2009;2(1):1-10.
22.Boeck S,Schulz C,Stieber P,Holdenrieder S,Weckbach S,Heinemann V.Assessing prognosis in metastatic pancreatic cancer by the serum tumor marker CA 19-9:pretreatment levels or kinetics during chemotherapy? Onkologie 2007;30(l-2):39-42.
23.Bootcov MR,Bauskin AR,Valenzuela SM,et al.MIC-1,a novel macrophage inhibitory cytokine,is a divergent member of the TGF-beta superfamily.Proc Natl Acad Sci U S A 1997;94(21):11514-9.
24.Schober A,Bottner M,Strelau J,et al.Expression of growth differentiation factor-15/ macrophage inhibitory cytokine-1(GDF-15/MIC-1) in the perinatal,adult,and injured rat brain.J Comp Neurol 2001;439(l):32-45.
25.Lee DH,Yang Y,Lee SJ,et al.Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system.Cancer Res 2003;63(15):4648-55.
26.Buckhaults P,Rago C,St Croix B,et al.Secreted and cell surface genes expressed in benign and malignant colorectal tumors.Cancer Res 2001;61(19):6996-7001.
27.Welsh JB,Sapinoso LM,Su AI,et al.Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer.Cancer Res 2001;61(16):5974-8.
28.Koopmann J,Buckhaults P,Brown DA,et al.Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.Clin Cancer Res 2004;10(7):2386-92.
29.Koopmann J,Rosenzweig CN,Zhang Z,et al.Serum markers in patients with resectable pancreatic adenocarcinoma:macrophage inhibitory cytokine 1 versus CA19-9.Clin Cancer Res 2006;12(2):442-6.
30.Brentnall TA,Brenner MP,Byrd DR,Haggitt RC,Kimmey MB.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer.Ann Intern Med 1999;131(4):247-55.
31.Canto MI,Goggins M,Yeo CJ,et al.Screening for pancreatic neoplasia in high-risk individuals:an EUS-based approach.Clin Gastroenterol Hepatol 2004;2(7):606-21.
32.Prall F,Nollau P,Neumaier M,et al.CD66a(BGP),an adhesion molecule of the carcinoembryonic antigen family,is expressed in epithelium,endothelium,and myeloid cells in a wide range of normal human tissues.J Histochem Cytochem 1996;44(1):35-41.
33.Simeone DM,Ji B,Banerjee M,et al.CEACAM1,a novel serum biomarker for pancreatic cancer.Pancreas 2007;34(4):436-43.
34.金呈强 刘仿,王文涓.癌胚抗原相关细胞黏附分子1(CEACAM1)的研究进展.中国癌症杂志2008;18(4):310-4.
35.Zhang L,Zhou W,Velculescu VE,et al.Gene expression profiles in normal and cancer cells.Science 1997;276(5316):1268-72.
36.Neumaier M,Paululat S,Chan A,Matthaes P,Wagener C.Biliary glycoprotein,a potential human cell adhesion molecule,is down-regulated in colorectal carcinomas.Proc Natl Acad Sci U S A 1993;90(22):10744-8.
37.Riethdorf L,Lisboa BW,Henkel U,Naumann M,Wagener C,Loning T.Differential expression of CD66a(BGP),a cell adhesion molecule of the carcinoembryonic antigen family,in benign,premalignant,and malignant lesions of the human mammary gland.J Histochem Cytochem 1997;45(7):957-63.
38.Kleinerman DI,Troncoso P,Lin SH,et al.Consistent expression of an epithelial cell adhesion molecule(C-CAM) during human prostate development and loss of expression in prostate cancer:implication as a tumor suppressor.Cancer research 1995;55(6):1215-20.
39.Laack E,Nikbakht H,Peters A,et al.Expression of CEACAM1 in adenocarcinoma of the lung:a factor of independent prognostic significance.J Clin Oncol 2002;20(21):4279-84.
40.Sienel W,Dango S,Woelfle U,et al.Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 promotes progression of non-small cell lung cancer.Clin Cancer Res 2003;9(6):2260-6.
41.Thies A,Moll I,Berger J,et al.CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease.J Clin Oncol 2002;20(10):2530-6.
42.Logsdon CD,Simeone DM,Binkley C,et al.Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer.Cancer Res 2003;63(10):2649-57.
43.Andrianifahanana M,Moniaux N,Schmied BM,et al.Mucin(MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis:a potential role of MUC4 as a tumor marker of diagnostic significance.Clin Cancer Res 2001;7(12):4033-40.
44.Hollingsworth MA,Swanson BJ.Mucins in cancer:protection and control of the cell surface.Nat Rev Cancer 2004;4(l):45-60.
45.Gold DV,Modrak DE,Ying Z,Cardillo TM,Sharkey RM,Goldenberg DM.New MUC1 serum immunoassay differentiates pancreatic cancer from pancreatitis.J Clin Oncol 2006;24(2):252-8.
46.Nakashima M,Sonoda K,Watanabe T.Inhibition of cell growth and induction of apoptotic cell death by the human tumor-associated antigen RCAS1.Nat Med 1999;5(8):938-42.
47.Akashi T,Oimomi H,Nishiyama K,et al.Expression and diagnostic evaluation of the human tumor-associated antigen RCAS1 in pancreatic cancer.Pancreas 2003;26(1):49-55.
48.Yamaguchi K,Enjoji M,Nakashima M,Nakamuta M,Watanabe T,Tanaka M.Novel serum tumor marker,RCAS1,in pancreatic diseases.World J Gastroenterol 2005;11(33):5199-202.
49.Ozkan H,Akar T,Koklu S,Coban S.Significance of serum receptor-binding cancer antigen(RCAS1) in pancreatic cancer and benign pancreatobiliary diseases.Pancreatology 2006;6(4):268-72.
50.Mazurek S,Boschek CB,Hugo F,Eigenbrodt E.Pyruvate kinase type M2 and its role in tumor growth and spreading.Semin Cancer Biol 2005;15(4):300-8.
51.Ventrucci M,Cipolla A,Racchini C,Casadei R,Simoni P,Gullo L.Tumor M2-pyruvate kinase,a new metabolic marker for pancreatic cancer.Dig Dis Sci 2004;49(7-8):1149-55.
52.Kumar Y,Gurusamy K,Pamecha V,Davidson BR.Tumor M2-pyruvate kinase as tumor marker in exocrine pancreatic cancer a meta-analysis.Pancreas 2007;35(2):114-9.
53.Novotny I,Dite P,Dastych M,et al.Tumor marker M2-pyruvate-kinase in differential diagnosis of chronic pancreatitis and pancreatic cancer.Hepatogastroenterology2008;55(85):1475-7.
54.Burris HA,3rd,Moore MJ,Andersen J,et al.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer:a randomized trial.J Clin Oncol 1997;15(6):2403-13.
55.Hidalgo M,Castellano D,Paz-Ares L,et al.Phase Ⅰ-Ⅱ study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.J Clin Oncol 1999;17(2):585-92.
56.Crino L,Mosconi AM,Calandri C,et al.Gemcitabine in advanced pancreatic cancer:a phase II trial.Am J Clin Oncol 2001;24(3):296-8.
57.Heinemann V.Gemcitabine:progress in the treatment of pancreatic cancer.Oncology 2001;60(1):8-18.
58.Eckel F,Schmelz R,Erdmann J,Mayr M,Lersch C.Phase Ⅱ trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma.Cancer Invest 2003;21(5):690-4.
59.Kleespies A,Jauch KW,Bruns CJ.Tyrosine kinase inhibitors and gemcitabine:new treatment options in pancreatic cancer? Drug Resist Updat 2006;9(1-2):1-18.
60.Saif MW,Karapanagiotou L,Syrigos K.Genetic alterations in pancreatic cancer.World J Gastroenterol 2007;13(33):4423-30.
61.Almoguera C,Shibata D,Forrester K,Martin J,Arnheim N,Perucho M.Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.Cell 1988;53(4):549-54.
62.Di Fiore F,Blanchard F,Charbonnier F,et al.Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy.Br J Cancer 2007;96(8):1166-9.
63.Eberhard DA,Johnson BE,Amler LC,et al.Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.J Clin Oncol 2005;23(25):5900-9.
64.Hruban RH,van Mansfeld AD,Offerhaus GJ,et al.K-ras oncogene activation in adenocarcinoma of the human pancreas.A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization.Am J Pathol 1993;143(2):545-54.
65.Kawesha A,Ghaneh P,Andren-Sandberg A,et al.K-ras oncogene subtype mutations are associated with survival but not expression of p53,pl6(INK4A),p21(WAF-l),cyclin Dl,erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma.Int J Cancer 2000;89(6):469-74.
66.Rozenblum E,Schutte M,Goggins M,et al.Tumor-suppressive pathways in pancreatic carcinoma.Cancer Res 1997;57(9):1731-4.
67.Smit VT,Boot AJ,Smits AM,Fleuren GJ,Cornelisse CJ,Bos JL.KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas.Nucleic Acids Res 1988;16(16):7773-82.
68.van Heek T,Rader AE,Offerhaus GJ,et al.K-ras,p53,and DPC4(MAD4) alterations in fine-needle aspirates of the pancreas:a molecular panel correlates with and supplements cytologic diagnosis.Am J Clin Pathol 2002;117(5):755-65.
69.Safran H,Steinhoff M,Mangray S,et al.Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma.Am J Clin Oncol 2001;24(5):496-9.
70.Talar-Wojnarowska R,Gasiorowska A,Smolarz B,et al.Clinical significance of K-ras and c-erbB-2 mutations in pancreatic adenocarcinoma and chronic pancreatitis.Int J Gastrointest Cancer 2005;35(1):33-41.
71.Tsiambas E,Karameris A,Dervenis C,et al.HER2/neu expression and gene alterations in pancreatic ductal adenocarcinoma:a comparative immunohistochemistry and chromogenic in situ hybridization study based on tissue microarrays and computerized image analysis.Jop 2006;7(3):283-94.
72.Dong M,Nio Y,Guo KJ,Tamura K,Tian YL,Dong YT.Epidermal growth factor and its receptor as prognostic indicators in Chinese patients with pancreatic cancer.Anticancer Res 1998;18(6B):4613-9.
73.Garcea G,Neal CP,Pattenden CJ,Steward WP,Berry DP.Molecular prognostic markers in pancreatic cancer:a systematic review.Eur J Cancer 2005;41(15):2213-36.
74.Bloomston M,Bhardwaj A,Ellison EC,Frankel WL.Epidermal growth factor receptor expression in pancreatic carcinoma using tissue microarray technique.Dig Surg 2006;23(l-2):74-9.
75.Borja-Cacho D,Jensen EH,Saluja AK,Buchsbaum DJ,Vickers SM.Molecular targeted therapies for pancreatic cancer.Am J Surg 2008;196(3):430-41.
76.Molina MA,Sitja-Arnau M,Lemoine MG,Frazier ML,Sinicrope FA.Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines:growth inhibition by nonsteroidal anti-inflammatory drugs.Cancer Res 1999;59(17):4356-62.
77.Okami J,Yamamoto H,Fujiwara Y,et al.Overexpression of cyclooxygenase-2 in carcinoma of the pancreas.Clin Cancer Res 1999;5(8):2018-24.
78.Tucker ON,Dannenberg A J,Yang EK,et al.Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer.Cancer Res 1999;59(5):987-90.
79.Fujioka S,Selabas GM,Schmidt C,et al.Function of nuclear factor kappaB in pancreatic cancer metastasis.Clin Cancer Res 2003;9(1):346-54.
80.Saha D,Datta PK,Beauchamp RD.Oncogenic ras represses transforming growth factor-beta /Smad signaling by degrading tumor suppressor Smad4.J Biol Chem 2001;276(31):29531-7.
81.李振宇,徐文静.K—ras基因与胰腺癌关系.现代中西医结合杂志2007;16(20):2947-9.
82.Sepp-Lorenzino L,Ma Z,Rands E,et al.A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines.Cancer Res 1995;55(22):5302-9.
83.Crul M,de Klerk GJ,Swart M,et al.Phase Ⅰ clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer.J Clin Oncol 2002;20(11):2726-35.
84.Johnston SR,Hickish T,Ellis P,et al.Phase Ⅱ study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor,R115777,in advanced breast cancer.J Clin Oncol 2003;21(13):2492-9.
85.Zujewski J,Horak ID,Bol CJ,et al.Phase Ⅰand pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.J Clin Oncol 2000;18(4):927-41.
86.Macdonald JS,McCoy S,Whitehead RP,et al.A phase Ⅱ study of farnesyl transferase inhibitor R115777 in pancreatic cancer:a Southwest oncology group (SWOG 9924) study.Invest New Drugs 2005;23(5):485-7.
87.Van Cutsem E,van de Velde H,Karasek P,et al.Phase Ⅲ trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer.J Clin Onco12004;22(8):1430-8.
88.Xiong HQ,Abbruzzese JL.Epidermal growth factor receptor-targeted therapy for pancreatic cancer.Semin Oncol 2002;29(5 Suppl 14):31-7.
89.Bruns CJ,Harbison MT,Davis DW,et al.Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms.Clin Cancer Res 2000;6(5):1936-48.
90.Arnoletti JP,Buchsbaum DJ,Huang ZQ,et al.Mechanisms of resistance to Erbitux(anti-epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells.J Gastrointest Surg 2004;8(8):960-9;discussion 9-70.
91.Buchsbaum DJ,Bonner JA,Grizzle WE,et al.Treatment of pancreatic cancer xenografts with Erbitux(IMC-C225) anti-EGFR antibody,gemcitabine,and radiation.Int J Radiat Oncol Biol Phys 2002;54(4):1180-93.
92.Overholser JP,Prewett MC,Hooper AT,Waksal HW,Hicklin DJ.Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice.Cancer 2000;89(1):74-82.
93.Xiong HQ,Rosenberg A,LoBuglio A,et al.Cetuximab,a monoclonal antibody targeting the epidermal growth factor receptor,in combination with gemcitabine for advanced pancreatic cancer:a multicenter phase Ⅱ Trial.J Clin Oncol 2004;22(13):2610-6.
94.Cascinu S,Berardi R,Labianca R,et al.Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer:a randomised,multicentre,phase Ⅱ trial.Lancet Oncol 2008;9(1):39-44.
95.Kullmann F,Hollerbach S,Dollinger MM,et al.Cetuximab plus gemcitabine/oxaliplatin(GEMOXCET) in first-line metastatic pancreatic cancer:a multicentre phase Ⅱ study.Br J Cancer 2009;100(7):1032-6.
96.Philip PA BJ,Fenoglio-Preiser C,et al.Phase Ⅲ study of gemcitabine[G]plus cetuximab[C]versus gemcitabine in patients[pts]with locally advanced or metastatic pancreatic adenocarcinoma[PC]:SWOG S0205 study.J Clin Oncol(Meeting Abstracts) 2007;25:4509.
97.Danovi SA,Wong HH,Lemoine NR.Targeted therapies for pancreatic cancer.Br Med Bull 2008;87:97-130.
98.Kleespies A,Ischenko I,Eichhorn ME,et al.Matuzumab short-term therapy in experimental pancreatic cancer:prolonged antitumor activity in combination with gemcitabine.Clin Cancer Res 2008;14(17):5426-36.
99.Graeven U,Kremer B,Sudhoff T,et al.Phase Ⅰ study of the humanised anti-EGFR monoclonal antibody matuzumab(EMD 72000) combined with gemcitabine in advanced pancreatic cancer.Br J Cancer 2006;94(9):1293-9.
100.Strimpakos A,Saif MW,Syrigos KN.Pancreatic cancer:from molecular pathogenesis to targeted therapy.Cancer Metastasis Rev 2008;27(3):495-522.
101.Moore MJ,Goldstein D,Hamm J,et al.Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer:a phase Ⅲ trial of the National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol 2007;25(15):1960-6.
102.Kulke MH,Blaszkowsky LS,Ryan DP,et al.Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer.J Clin Oncol 2007;25(30):4787-92.
103.Ono M,Kuwano M.Molecular mechanisms of epidermal growth factor receptor(EGFR) activation and response to gefitinib and other EGFR-targeting drugs.Clin Cancer Res 2006;12(24):7242-51.
104.Maurel J,Martin-Richard M,Conill C,et al.Phase Ⅰ trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion,in locally advanced pancreatic cancer.Int J Radiat Oncol Biol Phys 2006;66(5):1391-8.
105.Czito BG,Willett CG,Bendell JC,et al.Increased toxicity with gefitinib,capecitabine,and radiation therapy in pancreatic and rectal cancer:phase I trial results.J Clin Oncol 2006;24(4):656-62.
106.Hanahan D,Weinberg RA.The hallmarks of cancer.Cell 2000;100(1):57-70.
107.Cohen MH,Gootenberg J,Keegan P,Pazdur R.FDA drug approval summary:bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer.Oncologist 2007;12(3):356-61.
108.Kindler HL,Friberg G,Singh DA,et al.Phase Ⅱ trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer.J Clin Oncol 2005;23(31):8033-40.
109.Kindler HL ND,Hollis DR,et al.A double-blind,placebo-controlled,randomized phase Ⅲ trial of gemcitabine(G) plus bevacizumab(B) versus gemcitabine plus placebo(P) in patients(pts) with advanced pancreatic cancer(PC):A preliminary analysis of Cancer and Leukemia Group B(CALGB) 80303[abstract].In:American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2007;19-21 January 2007;Orlando Alexandria:American Society of Clinical Oncology;2007 Abstr 108.
110.Van Cutsem E,Vervenne WL,Bennouna J,et al.Phase Ⅲ trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.J Clin Oncol 2009;27(13):2231-7.
111.Chambers AF,Matrisian LM.Changing views of the role of matrix metalloproteinases in metastasis.J Natl Cancer Inst 1997;89(17):1260-70.
112.Bramhall SR,Schulz J,Nemunaitis J,Brown PD,Baillet M,Buckels JA.A double-blind placebo-controlled,randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer.Br J Cancer 2002;87(2):161-7.
113.Bramhall SR,Rosemurgy A,Brown PD,Bowry C,Buckels JA.Marimastat as first-line therapy for patients with unresectable pancreatic cancer:a randomized trial.J Clin Oncol 2001;19(15):3447-55.
114.Moore MJ,Hamm J,Dancey J,et al.Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas:a phase Ⅲ trial of the National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol 2003;21(17):3296-302.
115.Raut CP,Nawrocki S,Lashinger LM,et al.Celecoxib inhibits angiogenesis by inducing endothelial cell apoptosis in human pancreatic tumor xenografts.Cancer Biol Ther 2004;3(12):1217-24.
116.Wei D,Wang L,He Y,Xiong HQ,Abbruzzese JL,Xie K.Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Spl transcription factor activity.Cancer Res 2004;64(6):2030-8.
117.Crane CH,Mason K,Janjan NA,Milas L.Initial experience combining cyclooxygenase-2 inhibition with chemoradiation for locally advanced pancreatic cancer.Am J Clin Oncol 2003;26(4):S81-4.
118.Ferrari V,Valcamonico F,Amoroso V,et al.Gemcitabine plus celecoxib(GECO) in advanced pancreatic cancer:a phase Ⅱ trial.Cancer chemotherapy and pharmacology 2006;57(2):185-90.
119.Kim J,Reber HA,Dry SM,et al.Unfavourable prognosis associated with K-ras gene mutation in pancreatic cancer surgical margins.Gut 2006;55(11):1598-605.
120.Liang JJ,Wang H,Rashid A,et al.Expression of MAP4K4 is associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma.Clin Cancer Res 2008;14(21):7043-9.
121.Bishop AL,Hall A.Rho GTPases and their effector proteins.The Biochemical journal 2000;348 Pt 2:241-55.
122.Dittert DD,Kielisch C,Alldinger I,et al.Prognostic significance of immunohisto chemical RhoA expression on survival in pancreatic ductal adenocarcinoma:a high-throughput analysis.Human pathology 2008;39(7):1002-10.
123.尹义梅,穆建平,张晓岚.含缬酪肽蛋白与消化系统肿瘤.世界华人消化杂志2005,13(22):2672-6.
124.Saitou M,Goto M,Horinouchi M,et al.MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas.Journal of clinical pathology 2005;58(8):845-52.
2.张思维,陈万青,孔灵芝,等。.中国部分市县1998～2002年恶性肿瘤的发病与死亡.中国肿瘤2006;15(7):430-48.
3.Maitra A,Adsay NV,Argani P,et al.Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray.Mod Pathol 2003;16(9):902-12.
4.Harada T,Okita K,Shiraishi K,et al.Detection of genetic alterations in pancreatic cancers by comparative genomic hybridization coupled with tissue microdissection and degenerate oligonucleotide primed polymerase chain reaction.Oncology 2002;62(3):251-8.
5.Gorunova L,Hoglund M,Andren-Sandberg A,et al.Cytogenetic analysis of pancreatic carcinomas:intratumor heterogeneity and nonrandom pattern of chromosome aberrations.Genes,chromosomes & cancer 1998;23(2):81-99.
6.Harada T,Baril P,Gangeswaran R,et al.Identification of genetic alterations in pancreatic cancer by the combined use of tissue microdissection and array-based comparative genomic hybridisation.British journal of cancer 2007;96(2):373-82.
7.Harada T,Chelala C,Bhakta V,et al.Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays.Oncogene 2008;27(13):1951-60.
8.Harada T,Chelala C,Crnogorac-Jurcevic T,Lemoine NR.Genome-wide analysis of pancreatic cancer using microarray-based techniques.Pancreatology 2009;9(1-2):13-24.
9.Fritz S,Fernandez-del Castillo C,Mino-Kenudson M,et al.Global genomic analysis of intraductal papillary mucinous neoplasms of the pancreas reveals significant molecular differences compared to ductal adenocarcinoma.Annals of surgery 2009;249(3):440-7.
10.Ostroverkhova NV,Nazarenko SA,Cheremnykh AD.[Comparative genomic hybridization as a new method for detection of genomic imbalance].Genetika 2002;38(2):149-60.
11.Lockwood WW,Chari R,Chi B,Lam WL.Recent advances in array comparative genomic hybridization technologies and their applications in human genetics.Eur J Hum Genet 2006;14(2):139-48.
12.Kallioniemi A.CGH microarrays and cancer.Current opinion in biotechnology 2008;19(1):36-40.
13.Davies JJ,Wilson IM,Lam WL.Array CGH technologies and their applications to cancer genomes.Chromosome Res 2005;13(3):237-48.
14.Pinkel D,Albertson DG.Comparative genomic hybridization.Annual review of genomics and human genetics 2005;6:331-54.
15.Shinawi M,Cheung SW.The array CGH and its clinical applications.Drug discovery today 2008;13(17-18):760-70.
16.Pfister S,Remke M,Benner A,et al.Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci.J Clin Oncol 2009;27(10):1627-36.
17.Strefford JC,Parker H.Array-based comparative genomic hybridization as a tool for analyzing the leukemia genome.Methods in molecular biology(Clifton,NJ 2009;538:151-77.
18.Santos SC,Cavalli IJ,Ribeiro EM,et al.Patterns of DNA copy number changes in sentinel lymph node breast cancer metastases.Cytogenetic and genome research 2008;122(1):16-21.
19.Huang J,Pang J,Watanabe T,Ng HK,Ohgaki H.Whole genome amplification for array comparative genomic hybridization using DNA extracted from formalin-fixed,paraffin-embedded histological sections.J Mol Diagn 2009;11(2):109-16.
20.Bauer VL,Braselmann H,Henke M,et al.Chromosomal changes characterize head and neck cancer with poor prognosis.Journal of molecular medicine(Berlin,Germany) 2008;86(12):1353-65.
21.Nowak NJ,Gaile D,Conroy JM,et al.Genome-wide aberrations in pancreatic adenocarcinoma.Cancer genetics and cytogenetics 2005;161(l):36-50.
22.Heidenblad M,Schoenmakers EF,Jonson T,et al.Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines.Cancer research 2004;64(9):3052-9.
23.Bashyam MD,Bair R,Kim YH,et al.Array-based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer.Neoplasia(New York,NY 2005;7(6):556-62.
24.Gysin S,Rickert P,Kastury K,McMahon M.Analysis of genomic DNA alterations and mRNA expression patterns in a panel of human pancreatic cancer cell lines.Genes,chromosomes & cancer 2005;44(1):37-51.
25.Loukopoulos P,Shibata T,Katoh H,et al.Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinoma:identification of genetic indicators that predict patient outcome.Cancer science 2007;98(3):392-400.
26.Silasi DA,Alvero AB,Mor J,et al.Detection of cancer-related proteins in fresh-frozen ovarian cancer samples using laser capture microdissection.Methods in molecular biology(Clifton,NJ 2008;414:35-45.
27.Hergenhahn M,Kenzelmann M,Grone HJ.Laser-controlled microdissection of tissues opens a window of new opportunities.Pathology,research and practice 2003;199(6):419-23.
28.Fuller AP,Palmer-Toy D,Erlander MG,Sgroi DC.Laser capture microdissection and advanced molecular analysis of human breast cancer.Journal of mammary gland biology and neoplasia 2003;8(3):335-45.
29.Bilimoria KY,Bentrem DJ,Ko CY,et al.Validation of the 6th edition AJCC Pancreatic Cancer Staging System:report from the National Cancer Database.Cancer 2007;110(4):738-44.
30.Niederhuber JE,Brennan MF,Menck HR.The National Cancer Data Base report on pancreatic cancer.Cancer 1995;76(9):1671-7.
31.沈魁 马刚,郭克见．胰腺癌诊断与外科治疗现状1008例调查分析．中华外科杂志 1998；36(12)：766-9．
32.Hidalgo M,Castellano D,Paz-Ares L,et al.Phase Ⅰ-Ⅱ study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.J Clin Oncol 1999;17(2):585-92.
33.Crino L,Mosconi AM,Calandri C,et al.Gemcitabine in advanced pancreatic cancer:a phase II trial.Am J Clin Oncol 2001;24(3):296-8.
34.Heinemann V.Gemcitabine:progress in the treatment of pancreatic cancer.Oncology 2001;60(1):8-18.
35.Eckel F,Schmelz R,Erdmann J,Mayr M,Lersch C.Phase Ⅱ trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma.Cancer Invest 2003;21(5):690-4.
36.Kleespies A,Jauch KW,Bruns CJ.Tyrosine kinase inhibitors and gemcitabine:new treatment options in pancreatic cancer? Drug Resist Updat 2006;9(1-2):1-18.
37.Saif MW,Karapanagiotou L,Syrigos K.Genetic alterations in pancreatic cancer.World J Gastroenterol 2007;13(33):4423-30.
38.Moore MJ,Goldstein D,Hamm J,et al.Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer:a phase Ⅲ trial of the National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol 2007;25(15):1960-6.
39.Jong K,Marchiori E,Meijer G,Vaart AV,Ylstra B.Breakpoint identification and smoothing of array comparative genomic hybridization data.Bioinformatics(Oxford,England) 2004;20(18):3636-7.
40.Chari R,Lockwood WW,Lam WL.Computational Methods for the Analysis of Array Comparative Genomic Hybridization.Cancer informatics 2006;2:48-58.
41.Boehm JS,Zhao JJ,Yao J,et al.Integrative genomic approaches identify IKBKE as a breast cancer oncogene.Cell 2007;129(6):1065-79.
42.Agami R.All roads lead to IKKepsilon.Cell 2007;129(6):1043-5.
43.Reiter RE,Gu Z,Watabe T,et al.Prostate stem cell antigen:a cell surface marker overexpressed in prostate cancer.Proceedings of the National Academy of Sciences of the United States of America 1998;95(4):1735-40.
44.郎根强 孙盈浩．前列腺干细胞抗原与前列腺癌．国外医学泌尿系统分册2002；22(5)：280-2．
45.Sardana G,Do well B,Diamandis EP.Emerging bio markers for the diagnosis and prognosis of prostate cancer.Clinical chemistry 2008;54(12):1951-60.
46.Panteleakou Z,Lembessis P,Sourla A,et al.Detection of circulating tumor cells in prostate cancer patients:methodological pitfalls and clinical relevance.Molecular medicine(Cambridge,Mass 2009;15(3-4):101-14.
47.Argani P,Rosty C,Reiter RE,et al.Discovery of new markers of cancer through serial analysis of gene expression:prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma.Cancer research 2001;61(11):4320-4.
48.Cao D,Maitra A,Saavedra JA,Klimstra DS,Adsay NV,Hruban RH.Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms:additional evidence of different genetic pathways.Mod Pathol 2005;18(6):752-61.
49.Wente MN,Jain A,Kono E,et al.Prostate stem cell antigen is a putative target for immunotherapy in pancreatic cancer.Pancreas 2005;31(2):119-25.
50.McCarthy DM,Maitra A,Argani P,et al.Novel markers of pancreatic adenocarcinoma in fine-needle aspiration:mesothelin and prostate stem cell antigen labeling increases accuracy in cytologically borderline cases.Appl Immunohistochem Mol Morphol 2003;11(3):238-43.
51.Yong KT,Ding H,Roy I,et al.Imaging pancreatic cancer using bioconjugated InP quantum dots.ACS nano 2009;3(3):502-10.
52.Tanaka M,Komatsu N,Terakawa N,et al.Increased levels of IgG antibodies against peptides of the prostate stem cell antigen in the plasma of pancreatic cancer patients.Oncology reports 2007;18(1):161-6.
53.Foss CA,Fox JJ,Feldmann G,et al.Radiolabeled anti-claudin 4 and anti-prostate stem cell antigen:initial imaging in experimental models of pancreatic cancer.Mol Imaging 2007;6(2):131-9.
54.Rodriguez JA,Li M,Yao Q,Chen C,Fisher WE.Gene overexpression in pancreatic adenocarcinoma:diagnostic and therapeutic implications.World journal of surgery 2005;29(3):297-305.
55.Gu Z,Yamashiro J,Kono E,Reiter RE.Anti-prostate stem cell antigen monoclonal antibody 1G8 induces cell death in vitro and inhibits tumor growth in vivo via a Fc-independent mechanism.Cancer research 2005;65(20):9495-500.
56.Adsay NV,Basturk O,Cheng JD,Andea AA.Ductal neoplasia of the pancreas:nosologic,clinicopathologic,and biologic aspects.Seminars in radiation oncology 2005;15(4):254-64.
57.杨文彬 蔡锋,程传涛,曹罡,秦兆寅.人胰腺癌中前列腺干细胞抗原及紧密连接蛋白-4的表达.中国医学科学院学报2008;30(6):728-31.
58.Bustin M,Reeves R.High-mobility-group chromosomal proteins:architectural components that facilitate chromatin function.Progress in nucleic acid research and molecular biology 1996;54:35-100.
59.Motoyama K,Inoue H,Nakamura Y,Uetake H,Sugihara K,Mori M.Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family.Clin Cancer Res 2008;14(8):2334-40.
60.Hristov AC,Cope L,Reyes MD,et al.HMGA2 protein expression correlates with lymph node metastasis and increased tumor grade in pancreatic ductal adenocarcinoma.Mod Pathol 2009;22(1):43-9.
61.Abe N,Watanabe T,Suzuki Y,et al.An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue.British journal of cancer 2003;89(11):2104-9.
1.Jemal A,Siegel R,Ward E,et aI.Cancer statistics,2008.CA Cancer J Clin 2008;58(2):71-96.
2.张思维,陈万青,孔灵芝,等。中国部分市县1998～2002年恶性肿瘤的发病与死亡.中国肿瘤2006;15(7):430-48.
3.Katz MH,Hwang R,Fleming JB,Evans DB.Tumor-node-metastasis staging of pancreatic adenocarcinoma.CA:a cancer journal for clinicians 2008;58(2):111-25.
4.Bilimoria KY,Bentrem D J,Ko CY,et al.Validation of the 6th edition AJCC Pancreatic Cancer Staging System:report from the National Cancer Database.Cancer 2007;110(4):738-44.
5.Niederhuber JE,Brennan MF,Menck HR.The National Cancer Data Base report on pancreatic cancer.Cancer 1995;76(9):1671-7.
6.沈魁 马刚,郭克见.胰腺癌诊断与外科治疗现状1008例调查分析.中华外科杂志1998;36(12):766-9.
7.Richter A,Niedergethmann M,Sturm JW,Lorenz D,Post S,Trede M.Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head:25-year experience.World J Surg 2003;27(3):324-9.
8.Carpelan-Holmstrom M,Nordling S,Pukkala E,et al.Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry.Gut 2005;54(3):385-7.
9.Wagner M,Redaelli C,Lietz M,Seiler CA,Friess H,Buchler MW.Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma.Br J Surg 2004;91(5):586-94.
10.Ozkan H,Kaya M,Cengiz A.Comparison of tumor marker CA 242 with CA 19-9and carcinoembryonic antigen(CEA) in pancreatic cancer.Hepato-gastroenterology 2003;50(53):1669-74.
11.Grote T,Logsdon CD.Progress on molecular markers of pancreatic cancer.Curr Opin Gastroenterol 2007;23(5):508-14.
12.Goonetilleke KS,Siriwardena AK.Systematic review of carbohydrate antigen(CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer.Eur J Surg Oncol 2007;33(3):266-70.
13.Fry LC,Monkemuller K,Malfertheiner P.Molecular markers of pancreatic cancer:development and clinical relevance.Langenbecks Arch Surg 2008;393(6):883-90.
14.Goggins M.Molecular markers of early pancreatic cancer.J Clin Oncol 2005;23(20):4524-31.
15.Boeck S,Stieber P,Holdenrieder S,Wilkowski R,Heinemann V.Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer.Oncology 2006;70(4):255-64.
16.Locker GY,Hamilton S,Harris J,et al.ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer.J Clin Oncol 2006;24(33):5313-27.
17.Chang CY,Huang SP,Chiu HM,Lee YC,Chen MF,Lin JT.Low efficacy of serum levels of CA 19-9 in prediction of malignant diseases in asymptomatic population in Taiwan.Hepatogastroenterology 2006;53(67):l-4.
18.Ziske C,Schlie C,Gorschluter M,et al.Prognostic value of CA 19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine.Br J Cancer 2003;89(8):1413-7.
19.Ferrone CR,Finkelstein DM,Thayer SP,Muzikansky A,Fernandez-delCastillo C,Warshaw AL.Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma.J Clin Oncol 2006;24(18):2897-902.
20.Kilic M,Gocmen E,Tez M,Ertan T,Keskek M,Koc M.Value of preoperative serum CA 19-9 levels in predicting resectability for pancreatic cancer.Can J Surg 2006;49(4):241-4.
21.Liang JJ,Kimchi ET,Staveley-O'Carroll KF,Tan D.Diagnostic and prognostic biomarkers in pancreatic carcinoma.Int J Clin Exp Pathol 2009;2(1):1-10.
22.Boeck S,Schulz C,Stieber P,Holdenrieder S,Weckbach S,Heinemann V.Assessing prognosis in metastatic pancreatic cancer by the serum tumor marker CA 19-9:pretreatment levels or kinetics during chemotherapy? Onkologie 2007;30(l-2):39-42.
23.Bootcov MR,Bauskin AR,Valenzuela SM,et al.MIC-1,a novel macrophage inhibitory cytokine,is a divergent member of the TGF-beta superfamily.Proc Natl Acad Sci U S A 1997;94(21):11514-9.
24.Schober A,Bottner M,Strelau J,et al.Expression of growth differentiation factor-15/ macrophage inhibitory cytokine-1(GDF-15/MIC-1) in the perinatal,adult,and injured rat brain.J Comp Neurol 2001;439(l):32-45.
25.Lee DH,Yang Y,Lee SJ,et al.Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system.Cancer Res 2003;63(15):4648-55.
26.Buckhaults P,Rago C,St Croix B,et al.Secreted and cell surface genes expressed in benign and malignant colorectal tumors.Cancer Res 2001;61(19):6996-7001.
27.Welsh JB,Sapinoso LM,Su AI,et al.Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer.Cancer Res 2001;61(16):5974-8.
28.Koopmann J,Buckhaults P,Brown DA,et al.Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.Clin Cancer Res 2004;10(7):2386-92.
29.Koopmann J,Rosenzweig CN,Zhang Z,et al.Serum markers in patients with resectable pancreatic adenocarcinoma:macrophage inhibitory cytokine 1 versus CA19-9.Clin Cancer Res 2006;12(2):442-6.
30.Brentnall TA,Brenner MP,Byrd DR,Haggitt RC,Kimmey MB.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer.Ann Intern Med 1999;131(4):247-55.
31.Canto MI,Goggins M,Yeo CJ,et al.Screening for pancreatic neoplasia in high-risk individuals:an EUS-based approach.Clin Gastroenterol Hepatol 2004;2(7):606-21.
32.Prall F,Nollau P,Neumaier M,et al.CD66a(BGP),an adhesion molecule of the carcinoembryonic antigen family,is expressed in epithelium,endothelium,and myeloid cells in a wide range of normal human tissues.J Histochem Cytochem 1996;44(1):35-41.
33.Simeone DM,Ji B,Banerjee M,et al.CEACAM1,a novel serum biomarker for pancreatic cancer.Pancreas 2007;34(4):436-43.
34.金呈强 刘仿,王文涓.癌胚抗原相关细胞黏附分子1(CEACAM1)的研究进展.中国癌症杂志2008;18(4):310-4.
35.Zhang L,Zhou W,Velculescu VE,et al.Gene expression profiles in normal and cancer cells.Science 1997;276(5316):1268-72.
36.Neumaier M,Paululat S,Chan A,Matthaes P,Wagener C.Biliary glycoprotein,a potential human cell adhesion molecule,is down-regulated in colorectal carcinomas.Proc Natl Acad Sci U S A 1993;90(22):10744-8.
37.Riethdorf L,Lisboa BW,Henkel U,Naumann M,Wagener C,Loning T.Differential expression of CD66a(BGP),a cell adhesion molecule of the carcinoembryonic antigen family,in benign,premalignant,and malignant lesions of the human mammary gland.J Histochem Cytochem 1997;45(7):957-63.
38.Kleinerman DI,Troncoso P,Lin SH,et al.Consistent expression of an epithelial cell adhesion molecule(C-CAM) during human prostate development and loss of expression in prostate cancer:implication as a tumor suppressor.Cancer research 1995;55(6):1215-20.
39.Laack E,Nikbakht H,Peters A,et al.Expression of CEACAM1 in adenocarcinoma of the lung:a factor of independent prognostic significance.J Clin Oncol 2002;20(21):4279-84.
40.Sienel W,Dango S,Woelfle U,et al.Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 promotes progression of non-small cell lung cancer.Clin Cancer Res 2003;9(6):2260-6.
41.Thies A,Moll I,Berger J,et al.CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease.J Clin Oncol 2002;20(10):2530-6.
42.Logsdon CD,Simeone DM,Binkley C,et al.Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer.Cancer Res 2003;63(10):2649-57.
43.Andrianifahanana M,Moniaux N,Schmied BM,et al.Mucin(MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis:a potential role of MUC4 as a tumor marker of diagnostic significance.Clin Cancer Res 2001;7(12):4033-40.
44.Hollingsworth MA,Swanson BJ.Mucins in cancer:protection and control of the cell surface.Nat Rev Cancer 2004;4(l):45-60.
45.Gold DV,Modrak DE,Ying Z,Cardillo TM,Sharkey RM,Goldenberg DM.New MUC1 serum immunoassay differentiates pancreatic cancer from pancreatitis.J Clin Oncol 2006;24(2):252-8.
46.Nakashima M,Sonoda K,Watanabe T.Inhibition of cell growth and induction of apoptotic cell death by the human tumor-associated antigen RCAS1.Nat Med 1999;5(8):938-42.
47.Akashi T,Oimomi H,Nishiyama K,et al.Expression and diagnostic evaluation of the human tumor-associated antigen RCAS1 in pancreatic cancer.Pancreas 2003;26(1):49-55.
48.Yamaguchi K,Enjoji M,Nakashima M,Nakamuta M,Watanabe T,Tanaka M.Novel serum tumor marker,RCAS1,in pancreatic diseases.World J Gastroenterol 2005;11(33):5199-202.
49.Ozkan H,Akar T,Koklu S,Coban S.Significance of serum receptor-binding cancer antigen(RCAS1) in pancreatic cancer and benign pancreatobiliary diseases.Pancreatology 2006;6(4):268-72.
50.Mazurek S,Boschek CB,Hugo F,Eigenbrodt E.Pyruvate kinase type M2 and its role in tumor growth and spreading.Semin Cancer Biol 2005;15(4):300-8.
51.Ventrucci M,Cipolla A,Racchini C,Casadei R,Simoni P,Gullo L.Tumor M2-pyruvate kinase,a new metabolic marker for pancreatic cancer.Dig Dis Sci 2004;49(7-8):1149-55.
52.Kumar Y,Gurusamy K,Pamecha V,Davidson BR.Tumor M2-pyruvate kinase as tumor marker in exocrine pancreatic cancer a meta-analysis.Pancreas 2007;35(2):114-9.
53.Novotny I,Dite P,Dastych M,et al.Tumor marker M2-pyruvate-kinase in differential diagnosis of chronic pancreatitis and pancreatic cancer.Hepatogastroenterology2008;55(85):1475-7.
54.Burris HA,3rd,Moore MJ,Andersen J,et al.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer:a randomized trial.J Clin Oncol 1997;15(6):2403-13.
55.Hidalgo M,Castellano D,Paz-Ares L,et al.Phase Ⅰ-Ⅱ study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.J Clin Oncol 1999;17(2):585-92.
56.Crino L,Mosconi AM,Calandri C,et al.Gemcitabine in advanced pancreatic cancer:a phase II trial.Am J Clin Oncol 2001;24(3):296-8.
57.Heinemann V.Gemcitabine:progress in the treatment of pancreatic cancer.Oncology 2001;60(1):8-18.
58.Eckel F,Schmelz R,Erdmann J,Mayr M,Lersch C.Phase Ⅱ trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma.Cancer Invest 2003;21(5):690-4.
59.Kleespies A,Jauch KW,Bruns CJ.Tyrosine kinase inhibitors and gemcitabine:new treatment options in pancreatic cancer? Drug Resist Updat 2006;9(1-2):1-18.
60.Saif MW,Karapanagiotou L,Syrigos K.Genetic alterations in pancreatic cancer.World J Gastroenterol 2007;13(33):4423-30.
61.Almoguera C,Shibata D,Forrester K,Martin J,Arnheim N,Perucho M.Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.Cell 1988;53(4):549-54.
62.Di Fiore F,Blanchard F,Charbonnier F,et al.Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy.Br J Cancer 2007;96(8):1166-9.
63.Eberhard DA,Johnson BE,Amler LC,et al.Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.J Clin Oncol 2005;23(25):5900-9.
64.Hruban RH,van Mansfeld AD,Offerhaus GJ,et al.K-ras oncogene activation in adenocarcinoma of the human pancreas.A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization.Am J Pathol 1993;143(2):545-54.
65.Kawesha A,Ghaneh P,Andren-Sandberg A,et al.K-ras oncogene subtype mutations are associated with survival but not expression of p53,pl6(INK4A),p21(WAF-l),cyclin Dl,erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma.Int J Cancer 2000;89(6):469-74.
66.Rozenblum E,Schutte M,Goggins M,et al.Tumor-suppressive pathways in pancreatic carcinoma.Cancer Res 1997;57(9):1731-4.
67.Smit VT,Boot AJ,Smits AM,Fleuren GJ,Cornelisse CJ,Bos JL.KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas.Nucleic Acids Res 1988;16(16):7773-82.
68.van Heek T,Rader AE,Offerhaus GJ,et al.K-ras,p53,and DPC4(MAD4) alterations in fine-needle aspirates of the pancreas:a molecular panel correlates with and supplements cytologic diagnosis.Am J Clin Pathol 2002;117(5):755-65.
69.Safran H,Steinhoff M,Mangray S,et al.Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma.Am J Clin Oncol 2001;24(5):496-9.
70.Talar-Wojnarowska R,Gasiorowska A,Smolarz B,et al.Clinical significance of K-ras and c-erbB-2 mutations in pancreatic adenocarcinoma and chronic pancreatitis.Int J Gastrointest Cancer 2005;35(1):33-41.
71.Tsiambas E,Karameris A,Dervenis C,et al.HER2/neu expression and gene alterations in pancreatic ductal adenocarcinoma:a comparative immunohistochemistry and chromogenic in situ hybridization study based on tissue microarrays and computerized image analysis.Jop 2006;7(3):283-94.
72.Dong M,Nio Y,Guo KJ,Tamura K,Tian YL,Dong YT.Epidermal growth factor and its receptor as prognostic indicators in Chinese patients with pancreatic cancer.Anticancer Res 1998;18(6B):4613-9.
73.Garcea G,Neal CP,Pattenden CJ,Steward WP,Berry DP.Molecular prognostic markers in pancreatic cancer:a systematic review.Eur J Cancer 2005;41(15):2213-36.
74.Bloomston M,Bhardwaj A,Ellison EC,Frankel WL.Epidermal growth factor receptor expression in pancreatic carcinoma using tissue microarray technique.Dig Surg 2006;23(l-2):74-9.
75.Borja-Cacho D,Jensen EH,Saluja AK,Buchsbaum DJ,Vickers SM.Molecular targeted therapies for pancreatic cancer.Am J Surg 2008;196(3):430-41.
76.Molina MA,Sitja-Arnau M,Lemoine MG,Frazier ML,Sinicrope FA.Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines:growth inhibition by nonsteroidal anti-inflammatory drugs.Cancer Res 1999;59(17):4356-62.
77.Okami J,Yamamoto H,Fujiwara Y,et al.Overexpression of cyclooxygenase-2 in carcinoma of the pancreas.Clin Cancer Res 1999;5(8):2018-24.
78.Tucker ON,Dannenberg A J,Yang EK,et al.Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer.Cancer Res 1999;59(5):987-90.
79.Fujioka S,Selabas GM,Schmidt C,et al.Function of nuclear factor kappaB in pancreatic cancer metastasis.Clin Cancer Res 2003;9(1):346-54.
80.Saha D,Datta PK,Beauchamp RD.Oncogenic ras represses transforming growth factor-beta /Smad signaling by degrading tumor suppressor Smad4.J Biol Chem 2001;276(31):29531-7.
81.李振宇,徐文静.K—ras基因与胰腺癌关系.现代中西医结合杂志2007;16(20):2947-9.
82.Sepp-Lorenzino L,Ma Z,Rands E,et al.A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines.Cancer Res 1995;55(22):5302-9.
83.Crul M,de Klerk GJ,Swart M,et al.Phase Ⅰ clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer.J Clin Oncol 2002;20(11):2726-35.
84.Johnston SR,Hickish T,Ellis P,et al.Phase Ⅱ study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor,R115777,in advanced breast cancer.J Clin Oncol 2003;21(13):2492-9.
85.Zujewski J,Horak ID,Bol CJ,et al.Phase Ⅰand pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.J Clin Oncol 2000;18(4):927-41.
86.Macdonald JS,McCoy S,Whitehead RP,et al.A phase Ⅱ study of farnesyl transferase inhibitor R115777 in pancreatic cancer:a Southwest oncology group (SWOG 9924) study.Invest New Drugs 2005;23(5):485-7.
87.Van Cutsem E,van de Velde H,Karasek P,et al.Phase Ⅲ trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer.J Clin Onco12004;22(8):1430-8.
88.Xiong HQ,Abbruzzese JL.Epidermal growth factor receptor-targeted therapy for pancreatic cancer.Semin Oncol 2002;29(5 Suppl 14):31-7.
89.Bruns CJ,Harbison MT,Davis DW,et al.Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms.Clin Cancer Res 2000;6(5):1936-48.
90.Arnoletti JP,Buchsbaum DJ,Huang ZQ,et al.Mechanisms of resistance to Erbitux(anti-epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells.J Gastrointest Surg 2004;8(8):960-9;discussion 9-70.
91.Buchsbaum DJ,Bonner JA,Grizzle WE,et al.Treatment of pancreatic cancer xenografts with Erbitux(IMC-C225) anti-EGFR antibody,gemcitabine,and radiation.Int J Radiat Oncol Biol Phys 2002;54(4):1180-93.
92.Overholser JP,Prewett MC,Hooper AT,Waksal HW,Hicklin DJ.Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice.Cancer 2000;89(1):74-82.
93.Xiong HQ,Rosenberg A,LoBuglio A,et al.Cetuximab,a monoclonal antibody targeting the epidermal growth factor receptor,in combination with gemcitabine for advanced pancreatic cancer:a multicenter phase Ⅱ Trial.J Clin Oncol 2004;22(13):2610-6.
94.Cascinu S,Berardi R,Labianca R,et al.Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer:a randomised,multicentre,phase Ⅱ trial.Lancet Oncol 2008;9(1):39-44.
95.Kullmann F,Hollerbach S,Dollinger MM,et al.Cetuximab plus gemcitabine/oxaliplatin(GEMOXCET) in first-line metastatic pancreatic cancer:a multicentre phase Ⅱ study.Br J Cancer 2009;100(7):1032-6.
96.Philip PA BJ,Fenoglio-Preiser C,et al.Phase Ⅲ study of gemcitabine[G]plus cetuximab[C]versus gemcitabine in patients[pts]with locally advanced or metastatic pancreatic adenocarcinoma[PC]:SWOG S0205 study.J Clin Oncol(Meeting Abstracts) 2007;25:4509.
97.Danovi SA,Wong HH,Lemoine NR.Targeted therapies for pancreatic cancer.Br Med Bull 2008;87:97-130.
98.Kleespies A,Ischenko I,Eichhorn ME,et al.Matuzumab short-term therapy in experimental pancreatic cancer:prolonged antitumor activity in combination with gemcitabine.Clin Cancer Res 2008;14(17):5426-36.
99.Graeven U,Kremer B,Sudhoff T,et al.Phase Ⅰ study of the humanised anti-EGFR monoclonal antibody matuzumab(EMD 72000) combined with gemcitabine in advanced pancreatic cancer.Br J Cancer 2006;94(9):1293-9.
100.Strimpakos A,Saif MW,Syrigos KN.Pancreatic cancer:from molecular pathogenesis to targeted therapy.Cancer Metastasis Rev 2008;27(3):495-522.
101.Moore MJ,Goldstein D,Hamm J,et al.Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer:a phase Ⅲ trial of the National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol 2007;25(15):1960-6.
102.Kulke MH,Blaszkowsky LS,Ryan DP,et al.Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer.J Clin Oncol 2007;25(30):4787-92.
103.Ono M,Kuwano M.Molecular mechanisms of epidermal growth factor receptor(EGFR) activation and response to gefitinib and other EGFR-targeting drugs.Clin Cancer Res 2006;12(24):7242-51.
104.Maurel J,Martin-Richard M,Conill C,et al.Phase Ⅰ trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion,in locally advanced pancreatic cancer.Int J Radiat Oncol Biol Phys 2006;66(5):1391-8.
105.Czito BG,Willett CG,Bendell JC,et al.Increased toxicity with gefitinib,capecitabine,and radiation therapy in pancreatic and rectal cancer:phase I trial results.J Clin Oncol 2006;24(4):656-62.
106.Hanahan D,Weinberg RA.The hallmarks of cancer.Cell 2000;100(1):57-70.
107.Cohen MH,Gootenberg J,Keegan P,Pazdur R.FDA drug approval summary:bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer.Oncologist 2007;12(3):356-61.
108.Kindler HL,Friberg G,Singh DA,et al.Phase Ⅱ trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer.J Clin Oncol 2005;23(31):8033-40.
109.Kindler HL ND,Hollis DR,et al.A double-blind,placebo-controlled,randomized phase Ⅲ trial of gemcitabine(G) plus bevacizumab(B) versus gemcitabine plus placebo(P) in patients(pts) with advanced pancreatic cancer(PC):A preliminary analysis of Cancer and Leukemia Group B(CALGB) 80303[abstract].In:American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2007;19-21 January 2007;Orlando Alexandria:American Society of Clinical Oncology;2007 Abstr 108.
110.Van Cutsem E,Vervenne WL,Bennouna J,et al.Phase Ⅲ trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.J Clin Oncol 2009;27(13):2231-7.
111.Chambers AF,Matrisian LM.Changing views of the role of matrix metalloproteinases in metastasis.J Natl Cancer Inst 1997;89(17):1260-70.
112.Bramhall SR,Schulz J,Nemunaitis J,Brown PD,Baillet M,Buckels JA.A double-blind placebo-controlled,randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer.Br J Cancer 2002;87(2):161-7.
113.Bramhall SR,Rosemurgy A,Brown PD,Bowry C,Buckels JA.Marimastat as first-line therapy for patients with unresectable pancreatic cancer:a randomized trial.J Clin Oncol 2001;19(15):3447-55.
114.Moore MJ,Hamm J,Dancey J,et al.Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas:a phase Ⅲ trial of the National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol 2003;21(17):3296-302.
115.Raut CP,Nawrocki S,Lashinger LM,et al.Celecoxib inhibits angiogenesis by inducing endothelial cell apoptosis in human pancreatic tumor xenografts.Cancer Biol Ther 2004;3(12):1217-24.
116.Wei D,Wang L,He Y,Xiong HQ,Abbruzzese JL,Xie K.Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Spl transcription factor activity.Cancer Res 2004;64(6):2030-8.
117.Crane CH,Mason K,Janjan NA,Milas L.Initial experience combining cyclooxygenase-2 inhibition with chemoradiation for locally advanced pancreatic cancer.Am J Clin Oncol 2003;26(4):S81-4.
118.Ferrari V,Valcamonico F,Amoroso V,et al.Gemcitabine plus celecoxib(GECO) in advanced pancreatic cancer:a phase Ⅱ trial.Cancer chemotherapy and pharmacology 2006;57(2):185-90.
119.Kim J,Reber HA,Dry SM,et al.Unfavourable prognosis associated with K-ras gene mutation in pancreatic cancer surgical margins.Gut 2006;55(11):1598-605.
120.Liang JJ,Wang H,Rashid A,et al.Expression of MAP4K4 is associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma.Clin Cancer Res 2008;14(21):7043-9.
121.Bishop AL,Hall A.Rho GTPases and their effector proteins.The Biochemical journal 2000;348 Pt 2:241-55.
122.Dittert DD,Kielisch C,Alldinger I,et al.Prognostic significance of immunohisto chemical RhoA expression on survival in pancreatic ductal adenocarcinoma:a high-throughput analysis.Human pathology 2008;39(7):1002-10.
123.尹义梅,穆建平,张晓岚.含缬酪肽蛋白与消化系统肿瘤.世界华人消化杂志2005,13(22):2672-6.
124.Saitou M,Goto M,Horinouchi M,et al.MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas.Journal of clinical pathology 2005;58(8):845-52.