BRCA1、Ki-67在原发性上皮性卵巢癌中的表达及意义
|
摘要
目的:研究上皮性卵巢肿瘤中BRCAl、Ki-67的表达,探讨其在原发性上皮性卵巢癌(Primary Epithelial Ovarian Cancer)发生、发展及预后中的临床意义。
方法:联合应用组织芯片技术和免疫组化方法,检测BRCAl、Ki-67在62例原发性上皮性卵巢癌、14例交界性卵巢肿瘤、30例良性卵巢肿瘤中的表达。
结果:1.上皮性卵巢癌组织中BRCA l蛋白的异常表达率(80.6%)明显高于交界性肿瘤(14.3%)和良性卵巢肿瘤(0%),差别有高度统计学意义(P＜0.01)。卵巢癌组织中BRCAl的阳性表达率(59.7%)明显低于交界性肿瘤(92.9%)和良性卵巢肿瘤(100%),差别有统计学意义(P＜0.05)。2.BRCAl蛋白在卵巢癌组织学分级差的G_3组阳性表达率(31.6%)明显低于G_1、G_2组(分别为78.6%、69.0%),差别有统计学意义(P＜0.05),G_1和G_2比较差别没有统计学意义(P＞0.05)。BRCAl蛋白的表达与卵巢癌病理类型、临床分期无关。3.Ki-67在卵巢癌、交界性肿瘤、良性肿瘤中的阳性率分别为72.6%、21.4%、0%。两两比较差别均有统计学意义(P＜0.05)。尤其Ki-67在卵巢癌强阳性表达率(53.2%)显著高于交界性肿瘤和良性肿瘤(均为0%),差别有显著统计学意义(P＜0.01)。4.Ki-67在卵巢癌中、低分化G_2、G_3组中阳性表达率(分别为75.9%、94.7%)明显高于高分化G_1组(35.7%),差别有统计学意义(P＜0.05)。在临床分期Ⅲ期Ⅳ期中阳性表达率(84.6%)明显高于Ⅰ期Ⅱ期(52.2%),差别有统计学意义(P＜0.05)。Ki-67的表达与卵巢癌病理类型无关(P＞0.05)。5.卵巢癌中BRCAl蛋白和Ki-67蛋白的表达呈负相关(P＜0.05)。
结论:1.BRCAl蛋白在卵巢良性肿瘤中高表达于细胞核,而在卵巢癌中表达降低且多误表达于细胞浆,提示BRCAl亚细胞定位异常及BRCAl的表达下调可能是诱发卵巢癌的原因之一。2.BRCAl的表达与卵巢癌组织学分级有关,与临床分期、病理类型无关。提示BRCAl蛋白表达降低预示着卵巢癌的恶性程度增加,BRCAl蛋白的表达水平可作为评估卵巢癌恶性程度的指标之一。3.Ki-67在良性卵巢肿瘤中阴性表达,在交界性肿瘤中表达增高,而在卵巢癌中高表达,说明Ki-67能客观反映肿瘤细胞的增殖能力,可作为鉴别卵巢肿瘤性质的理想指标。4.Ki-67的表达与卵巢癌组织学分级、临床分期有关,与卵巢癌病理类型无关。提示Ki-67的过度表达预示着卵巢癌的恶性进展。5.在卵巢癌中BRCAl和Ki-67蛋白的表达呈负相关。联合检测BRCAl,Ki-67表达情况可以为卵巢癌早期筛查、估计恶性程度、判断预后及指导治疗方面提供理论依据。
Objective:To investigate the expression of BRCA1 and Ki-67 in epithelial ovarian tumor and the clinical significance in pathogenesis,progression and prognosis of primary epithelial ovarian cancer.
Methods:Tissue microarray technology and immunohistochemical method was used to detect the expression of BRCA1 and Ki-67 in 62 cases of primary epithelial ovarian cancer、14 cases of borderline epithelial ovarian tumor and 30 cases of benign epithelial ovarian tumor.
Results:①The abnormal expression rates of BRCA1 in epithelial ovarian cancer (80.6%) were significantly higher than that in borderline tumor(14.3%) and benign tumor(0%) of ovarian.The positive expression rates of BRCA1 in epithelial ovarian cancer(59.7%) were significantly lower than that in borderline tumor(92.9%) and benign tumor(100%) of ovarian.②The present data demonstrated that the expression of BRCA1 was not significantly correlated with surgical-pathologic staging and histological types of ovarian cancer(P＞0.05),but correlated with pathologic grade of ovarian cancer (P＜0.05).The expression of BRCA1 in G_3 was31.6%,which was remarkably reduced than in G_1,G_2(78.6%and 69.0%).③Immunohitochemical analysis also showed that Ki-67 expressed increased in cancer(72.6%) than in borderline tumors(21.4%) or benign tumors(0%) of ovarian(P＜0.05).Especially,the strong positive expression of Ki-67 was striking increased in ovarian cancer(53.2%) than in borderline ovarian tumor and benign ovarian tumor(0%)(P＜0.01).④A strong association has been observed between the expression of Ki-67 and surgical-pathologic staging,pathologic grade of ovarian cancer(P＜0.05),but not with hisological types(P＞0.05).The expression of Ki-67 was decreased in stageⅠ～Ⅱ(52.2%) than inⅢ～Ⅳ(84.6%).its levels were increased in grade G_(2-3)(75.9%and 94.7%) thanin G_1(35.7%).⑤.Expression of BRCA1 was negatively correlated with expression of Ki-67. Conclusion:①In benign ovarian tumor,expression of BRCA1 was stained in cell nucleus.However,in primary epithelial ovarian cancer,expression of BRCA1 was abnormal,such as decrease or absent in nucleus and mislocated in cytoplasm.The results suggest that anormaly of BRCA1 protein expression may be an important event in pathogenesis of the epithelial ovarian cancer.②The expression of BRCA1 protein was correlated with pathologic grade of ovarian cancer,which indicated the level of BRCA1 protein expression may be an indicatrix to judge the malignant degree of ovarian cancer.③Ki-67 expressed increased in cancer than in borderline tumors and benign tumors of ovarian,which demonstrated that the expression of Ki-67 can reflect reproductive activity of malignant cell and may be an ideal indicatrix to discriminate the property of ovarian tumor.④A strong association has been observed between the expression of Ki-67 and surgical-pathologic staging,pathologic grade of ovarian cancer,which indicates cell hyperproliferation is an important mechanism during the evolution of the ovarian cancer. The expression of Ki-67 may be an indicatrix to judge the malignant extent of ovarian cancer.⑤There is a significantly inverted relationship between the expression of BRCA1 protein and that of Ki-67 protein.The conjoined detection of BRCA1 and Ki-67 protein may be helpful to estimate malignant extent,judge prognosis and guide therapy of ovarian cancer.
方法:联合应用组织芯片技术和免疫组化方法,检测BRCAl、Ki-67在62例原发性上皮性卵巢癌、14例交界性卵巢肿瘤、30例良性卵巢肿瘤中的表达。
结果:1.上皮性卵巢癌组织中BRCA l蛋白的异常表达率(80.6%)明显高于交界性肿瘤(14.3%)和良性卵巢肿瘤(0%),差别有高度统计学意义(P＜0.01)。卵巢癌组织中BRCAl的阳性表达率(59.7%)明显低于交界性肿瘤(92.9%)和良性卵巢肿瘤(100%),差别有统计学意义(P＜0.05)。2.BRCAl蛋白在卵巢癌组织学分级差的G_3组阳性表达率(31.6%)明显低于G_1、G_2组(分别为78.6%、69.0%),差别有统计学意义(P＜0.05),G_1和G_2比较差别没有统计学意义(P＞0.05)。BRCAl蛋白的表达与卵巢癌病理类型、临床分期无关。3.Ki-67在卵巢癌、交界性肿瘤、良性肿瘤中的阳性率分别为72.6%、21.4%、0%。两两比较差别均有统计学意义(P＜0.05)。尤其Ki-67在卵巢癌强阳性表达率(53.2%)显著高于交界性肿瘤和良性肿瘤(均为0%),差别有显著统计学意义(P＜0.01)。4.Ki-67在卵巢癌中、低分化G_2、G_3组中阳性表达率(分别为75.9%、94.7%)明显高于高分化G_1组(35.7%),差别有统计学意义(P＜0.05)。在临床分期Ⅲ期Ⅳ期中阳性表达率(84.6%)明显高于Ⅰ期Ⅱ期(52.2%),差别有统计学意义(P＜0.05)。Ki-67的表达与卵巢癌病理类型无关(P＞0.05)。5.卵巢癌中BRCAl蛋白和Ki-67蛋白的表达呈负相关(P＜0.05)。
结论:1.BRCAl蛋白在卵巢良性肿瘤中高表达于细胞核,而在卵巢癌中表达降低且多误表达于细胞浆,提示BRCAl亚细胞定位异常及BRCAl的表达下调可能是诱发卵巢癌的原因之一。2.BRCAl的表达与卵巢癌组织学分级有关,与临床分期、病理类型无关。提示BRCAl蛋白表达降低预示着卵巢癌的恶性程度增加,BRCAl蛋白的表达水平可作为评估卵巢癌恶性程度的指标之一。3.Ki-67在良性卵巢肿瘤中阴性表达,在交界性肿瘤中表达增高,而在卵巢癌中高表达,说明Ki-67能客观反映肿瘤细胞的增殖能力,可作为鉴别卵巢肿瘤性质的理想指标。4.Ki-67的表达与卵巢癌组织学分级、临床分期有关,与卵巢癌病理类型无关。提示Ki-67的过度表达预示着卵巢癌的恶性进展。5.在卵巢癌中BRCAl和Ki-67蛋白的表达呈负相关。联合检测BRCAl,Ki-67表达情况可以为卵巢癌早期筛查、估计恶性程度、判断预后及指导治疗方面提供理论依据。
Objective:To investigate the expression of BRCA1 and Ki-67 in epithelial ovarian tumor and the clinical significance in pathogenesis,progression and prognosis of primary epithelial ovarian cancer.
Methods:Tissue microarray technology and immunohistochemical method was used to detect the expression of BRCA1 and Ki-67 in 62 cases of primary epithelial ovarian cancer、14 cases of borderline epithelial ovarian tumor and 30 cases of benign epithelial ovarian tumor.
Results:①The abnormal expression rates of BRCA1 in epithelial ovarian cancer (80.6%) were significantly higher than that in borderline tumor(14.3%) and benign tumor(0%) of ovarian.The positive expression rates of BRCA1 in epithelial ovarian cancer(59.7%) were significantly lower than that in borderline tumor(92.9%) and benign tumor(100%) of ovarian.②The present data demonstrated that the expression of BRCA1 was not significantly correlated with surgical-pathologic staging and histological types of ovarian cancer(P＞0.05),but correlated with pathologic grade of ovarian cancer (P＜0.05).The expression of BRCA1 in G_3 was31.6%,which was remarkably reduced than in G_1,G_2(78.6%and 69.0%).③Immunohitochemical analysis also showed that Ki-67 expressed increased in cancer(72.6%) than in borderline tumors(21.4%) or benign tumors(0%) of ovarian(P＜0.05).Especially,the strong positive expression of Ki-67 was striking increased in ovarian cancer(53.2%) than in borderline ovarian tumor and benign ovarian tumor(0%)(P＜0.01).④A strong association has been observed between the expression of Ki-67 and surgical-pathologic staging,pathologic grade of ovarian cancer(P＜0.05),but not with hisological types(P＞0.05).The expression of Ki-67 was decreased in stageⅠ～Ⅱ(52.2%) than inⅢ～Ⅳ(84.6%).its levels were increased in grade G_(2-3)(75.9%and 94.7%) thanin G_1(35.7%).⑤.Expression of BRCA1 was negatively correlated with expression of Ki-67. Conclusion:①In benign ovarian tumor,expression of BRCA1 was stained in cell nucleus.However,in primary epithelial ovarian cancer,expression of BRCA1 was abnormal,such as decrease or absent in nucleus and mislocated in cytoplasm.The results suggest that anormaly of BRCA1 protein expression may be an important event in pathogenesis of the epithelial ovarian cancer.②The expression of BRCA1 protein was correlated with pathologic grade of ovarian cancer,which indicated the level of BRCA1 protein expression may be an indicatrix to judge the malignant degree of ovarian cancer.③Ki-67 expressed increased in cancer than in borderline tumors and benign tumors of ovarian,which demonstrated that the expression of Ki-67 can reflect reproductive activity of malignant cell and may be an ideal indicatrix to discriminate the property of ovarian tumor.④A strong association has been observed between the expression of Ki-67 and surgical-pathologic staging,pathologic grade of ovarian cancer,which indicates cell hyperproliferation is an important mechanism during the evolution of the ovarian cancer. The expression of Ki-67 may be an indicatrix to judge the malignant extent of ovarian cancer.⑤There is a significantly inverted relationship between the expression of BRCA1 protein and that of Ki-67 protein.The conjoined detection of BRCA1 and Ki-67 protein may be helpful to estimate malignant extent,judge prognosis and guide therapy of ovarian cancer.
引文
1 Venkitaraman AR.Functions of BRCA1 and BRCA2 in the biological response to DNA damage.Mutat Res,2001,477(1-2):131-153.
2 Thomas JE,Smith M,Wonkinson JL,et aI.Induction of phosphorylation on BRCA1 during the cell cycle and after DNA damage.Cell growth Diff,1999,8:801-809.
3 Yarden RI,Brody LC.BRCA1 interacts with components of the histone complex.Proc Natl Acad,2001,96(9);4983-4988.
4 Zhang H.,Somasundaram,K.,Peng Y.,et al.BRCA1 physically associates with p53and stimulates it stranscriptional activity.Oncogene,2000,16(13):1713-1721
5 Bork P,Hofmann K,Bucher P,et al.A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins.FASEB J,1999,11(1):68-76.
6 Shao N,Chai YL,Shyam E,et al.Induction of apoptosis by the tumor suppressor protein BRCAI.Oncogene,1996,13(1):1-7。
7 Lynch HT,Watson P,Bewtra C.Hereditary ovarian cancer:hereterogenerty in age at diagnosis.Cancer.1991;67:1460.
8 沈铿,郎景和,黄荣丽,等.遗传性卵巢癌综合症的诊断和治疗对策.中华妇产科杂志,1996,31(12):732-735
9 Pual A.Russell,Paul D.P.Pharoah,Karen De Foy,et al.Frequent loss of BRCAI mRNA and protein expression in sporadic ovarian cancers.Int.J Cancer,2000,87:317-321.
10 Khoo US,Chan KY,Cheung AN,et al.2002.Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer:a founder mutation of BRCA1 identified in the Chinese population.Hum Murat,2002,19:307-308.
11 Pual A.Russell,Paul D.P.Pharoah,Karen De Foy,et al.Frequent loss of BRCA1mRNA and protein expression in sporadic ovarian cancers.Int.J Cancer,2000,87:317-321.
12 乐杰主编.妇产科学.人民卫生出版社,北京,第五版,1998.
13 Hall JM,Lee MK,Newman B,et al.Science,1990,250:1684-1689
14 Miki,Y.;Swensen,J.;Shattuck-Eidens,D.;Futreal,P.A.;Harshman,K.;Tavtigian,S.;Liu,Q.;Cochran,C.;Bennett,L.M.;Ding,W.;Bell,R.;Rosenthal,J.;and 33 others:A strong candidate for the breast and ovarian cancer susceptibility gene BRCA 1.Science,1 994,266:66.
15 Patrcia S.Granin exceptions in breast cancer? Nature Genet.1999:12:223-30.
16 Chen C,Chen C,Riley CJ,et al.Aberrant subcellular localization of BRCA1 in breast cancer.Science.1998;270(5233-5238):789-791.
17 JhamwarUM.BRCA1 in cancer cycle and genomic stability[J].Front Biosci,2003, 8:S1107-S1110.
18 FitzGerald MG MacDonaldDJ,KrainerM,et al。Germ-line BRCA1 mutations in Jewish and non- Jewish women with early-onset breast cancer[J].New Engl L Med,1996,334(3):143-149。
19 Peng-Hui Wang,Wen-Yann Shyong,Ywan Feng Li,Hsein-Hsiung Lee,Wen-Ying Tsai,Hsiang-Tai Chao,et al.BRCA 1 Mutations in Taiwanese with Epithelial Ovarian Carcinoma and Sporadic Primary Serous Peritoneal Carcinoma.Japanese Journal of Clinical Oncology,2000,30:343-348.
20 俞鸣,郝继辉,郝希山,焦振山,史玉荣.卵巢癌患者BRCA1基因突变及临床意义.中华妇产科杂志,2003,38(4):251
21 Russell PA,Pharoah PDD,Foy KD,et al。Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers。Int J Cancer,2000,87(3):317-321
22 Chen,Y;Farmer,A.A.;Chen,C.-F.;Jones,D.C.:Chen,P.-L.;Lee,W.-H.:BRCA1is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner.Cancer Res.56:3168-3172,2001.
23 Pual A.Russell,Paul D.P.Pharoah,Karen De Foy,Susan J.Ramus,Ian Symmonds,Snnie Wilson,et al.loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers.Int.J Cancer,2000,87:317-321
24 WenXin Zhang,Feng Lou,Jean J Lu.,Arimine Baltayan,Michael F.Press,Zuo-Feng Zhang,Malcolm C.Pike.Reduction of BRCAI Expression in Sporadic Ovarian Cancer.Gyneclolgy Oncology,2000,76:294-300
25 Thompson ME,Jenson RA,Obermiller PS,et al.Decreased expression of BRCA1accelerates growth and is often present during sporadic breast cancer progression[J].Nat Genet,2002,9(4):444-450
26 Tanimoto H,Underwood LJ,Shigemasa K,Parmley TH.The matrix metalloprotease pump-1(MMP-7,Matrilysin):A candidate/target for ovarian cancer detection and treatment.Tumor Biol,1999,20(2):88-98
27 Scholzen T,Gerdes J,The Ki-67 protein:from the known and the unknown[J].J Cell P hysiol,2000,182:311-322.
28 Suo Z,Karbovo E,Trope CG,et al.Papillary serous carcinoma of the ovary:an ultrastructural and immunohistochemical study[J].Obstet Gynecol,2002,100(2):281-287.
29 Korkolopoulou P,Vassilopoulos I,Konstantinidou A E,et al.The combined evaluation of p27 Kip1 and Ki-67 expressio provides independent information on overall survival of ovarian carcinoma patients[J].Gynecol Ontol,2002,85(3):404-414
30 周虹,杨竹,蔡汉钟等.Ki-67抗原在卵巢肿瘤组织中的表达及意义[J}重庆医学,2005,34(2):252-253.
31 罗军.应用组织芯片技术分析卵巢癌组织中Ki-67的表达.实用癌症杂志.2003,18(3): 263-266
32 Itamochi H, Kigawa J, Sugiyama T, et al. Low proliferation activity may be associated with chemoresi stance in clear cell carcinoma of the ovary [J]. Obstet Gynecol, 2002,100 (2):281-287.
33 Munstedt K, von Georgi R, Franke FE, et al. Correlation between MIB1 determined tumor growth fraction and incident of tumor recurrence in early ovarian carcinomas[J]. Cancer Invest, 2004, 22 (2):185—194.
34 Costa MJ, Walls J, Ames P, et al .Transformation in recurrent ovarian granulosa cell tumors: Ki67 (MIB-1) and p53 immunohistochemi-stry demonstrates a possible molecular basis for the poor histopathologic prediction of clinical behavior[J]. Hum Pathol, 1996, 27 (3):274-81.
35 Nocito A , Bubendorf L , Tinner EM , et al . Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade (J ) . J Pat hol ,2001 ,194(3) :349.
36 Camp RL , Charet te LA , Rimm DL , et al . Validation of tissue microarray technology in breast carcinoma (J ) . Lab Invest ,2000 ,80(12) :1943.
37 Moch H , Schrami P , Bubendorf L , et al . High2t hroughput tissue microarray analysis to evaluate genes uncovered by cDNA microarray screening in renal carcinoma (J ) .Am J Pat hol ,1999 ,154(4) :981.
1 Hall JM, Lee MK, Newman B, et al. Science, 1990, 250:1684-1689
2 Narod SA, Feunteun J, Lynch H 1, et al. Familial breast-ovarian cancer locus on chromosome 17ql2-q23. Lancet, 1991, 338(8759):82-83.
3 Miki, Y. ; Swensen, J. ; Shattuck-Eidens, D. ; Futreal, P. A. ; Harshman, K. ; Tavtigian,S. ; Liu, Q. ; Cochran, C. ; Bennett, L. M. ; Ding, W. ; Bell, R. ; Rosenthal, J. ; and 33 others:A strong candidate for the breast ard ovarian cancer susceptibility gene BRCA 1. Science, 1 994,266:66.
4 Lynch HT, Watson P, Bewtra C. Hereditary ovarian cancer: hereterogenerty in age at diagnosis. Cancer. 1991;67:1460.
5 Garvin AM, AttenhoferHaner M, Scott RJ. BRCA1 and BRCA2 analysis in 86 early onset breast/ovarian cancer patients. J Med Genet, 1997,34:990-995.
6 Patrcia S. Granin exceptions in breast cancer? Nature Genet. 1999; 12:223-30.
7 Chen C, Chen C, RileyCJ, et al. Aberrant subcellular localization of BRCA1 in breast cancer. Science. 2000;270(5233-5238):789-791.
8 Feunteun J. Breast cancer and genetic instability: the mo lecules behind the scenes (J) . Mo lecularM edicine Today, 1998, 6: 263
9 Hakem R et al.Cell, 1996; 85: 1009
10 Jernstrem H et al. Eur J Cancer, 1998; 34: 368
11 Scully R, Chen J, Ochs RL, et al。 Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage [J].Cell, 1997, 90 (3) :425-435
12 Yan Y, et al. [ J ] . J Biol Chem , 2002 , 277(36):33422-33430.
13 Harkin PD , et al. [ J ] . Cell , 1999 , 97 : 575-586.
14 Xu X, et al. [J ] . Nat Genet , 2001 ,28(3) :266-271.
15 Harkin PD , et al. [ J ] . Cell , 1999 , 97 : 575-586.
16 Thangaraju M, et al. [J ] . J Biol Chem , 2000 ,275 (43) :33487-33496.
17 Clarke LH. [J ] . Cancer Res , 2000 ,60 : 4993-5001.
18 Fan S , et al. [J ] . Science , 1999 , 284 (5418) :1354-1356.
19 Rattenborg T, et al. [J ] . Breast Cancer Res ,2002 ,4 : R12.
20 Chen JJ, Silver D, Cantor S, et alo BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway [J]。 Cancer Res, 1999, 59 (7Suppl) : 1752s-1756s
21 Zhong Q, Chen CF, Li S, et alo Association of BRCA1 with the hRad50-h Mrell-p95 complex and the DNA damage response [J] 。 Science, 1999, 285 (5428) : 747-750
22 Wang Y, Cortez D, Yazdi P, et al。 BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures [J] 。Genes Dev, 2000, 14 (8) : 927-939
23 MacLachlan TK, Takimoto R, El-DeiryWS. BRCA1 directs a selective p53 - dependent transcriptional response towards growth arrest and DNA repair targets[J].Mol Cell Biol,2002,22(12):4280-42851
24 Somasundaram K,Zhang H,Zeng YX,et al.Arrest of cell cycle by the tumor-supp ressor BRCA1 requires the CDK-inhibitor p21WAF1/Cip l[J].Nature,2002,389(6647):187-190.
25 Fan W,J in S,Tong T,et al.BRCA1 regulates GADD45 through its interactions with the OCT21 and CAAT motifs[J].J Biol Chem,2002,277(10):8061-8067.
26 Williamson EA,Dadmanesh F,Koeffler HP.BRCA1 transactivates the cyclin-dependent kinase inhibitor p27(Kipl)[J].Oncogene,2002,21(20):3199-3204.
27 Fan S,Wang J,Yuan R,et al.BRCA1 inhibition of estrogen receptor signaling in transfected cells[J].Science,1999,284(5418):1354-1359.
28 Zheng L,Annab LA,Afshari CA,et al.BRCA1 mediates ligand- independent transcrip tional rep ression of the estrogen receptor[J].Proc Natl Acad Sci USA,2001,98(17):9587-9593。
29 Rosen EM,Fan S,Pestell RG,et al.BRCA1 in hormone-responsive cancers[J].Trends EndocrinolMetab,2003,14(8):378.
30 Wang Q,Zhang H,Kajino K,et al.BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells[J].Oncogene,1998,17(15):1939-19451
31 Schuyer M,Bern EM,Is TP53 dysfunction required for BRCA1-associated carcinogenesis[J]Mol Cell Endorcrinol,1999,155(1-2):143
32 Fitzgerald MG MacDonald DJ,Krainer M,et al。Germ-line BRCA1 mutations in Jewish and non- Jewish women with early-onset breast cancer[J].New Engl L Med,1996,334(3):143-149。
33 Inoue R,Fukutomi T,Ushijima T,et al。Germline mutation of BRCA1 in Japanese breast cancer families[J].Cancer Res,1998,55(16):3521-3524.
34 丁晓曼,郎景和.BRCA1基因在早发性乳腺癌中的突变[J].中华医学杂志,2000,80(2):111-113.
35 赖春宁,江泽飞,宋三泰,等186例乳腺癌患者BRCA1基因突变检测[J]5中华肿瘤杂志,2001,23(6):483-485.
36 Peng-Hui Wang,Wen-Yann Shyong,Ywan Feng Li,Hsein-Hsiung Lee,Wen-Ying Tsai,Hsiang-Tai Chao,et al.BRCA 1 Mutations in Taiwanese with Epithelial Ovarian Carcinoma and Sporadic Primary Serous Peritoneal Carcinoma.Japanese Journal of Clinical Oncology,2000,30:343-348.
37 俞鸣,郝继辉,郝希山,焦振山,史玉荣.卵巢癌患者BRCA1基因突变及临床意义.中华妇产科杂志,2003,38(4):251
38 Chen,Y;Farmer,A.A.;Chen,C.-F.;Jones,D.C.;Chen,P.-L.;Lee,W.-H.:BRCA1is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner.Cancer Res.56:3168-3172,2001.
39 曾益新.肿瘤学[M].第2版,北京:人民卫生出版社,1999,69.
40 Hiroaki F,Manabu Y,Zhu XG,et al.Frequent genetic heterogeneity in the clonal evolution of gynecological carcinosarcoma and its influence on phenotypic diversity[J].Cancer Res,2000,60:114
41 Manderson EN,Presneau N,Provencher D,et al.Comparative analysis of loss of heterozygosity of specific chromosome 3,13,17,and X loci and TP53 mutations in human epithelial ovarian cancer[J].Mol Carcinog,2002,34(2):78
42 Bird AP.CpG-rich-island,and the function of DNAmethylation[J].Nature,1996;321:209-13.
43 EstellerM,Corn PG,Baylin SB,et al.A gene hypermethylation profile of human cancer [J].Cancer Res,2001;61:3225-9.
44 Carmen J,Costa I,Martins MC,et al.Detection of gene promoter hypermethy-lation in fine needle washings from breast lesions[J].Clin Cancer Res,2003;9:3413-7.
45 Showa Y,Oyama T,Nakajima T et al.BRCA1 expression status in relation to DNA methylation of BRCA1 promoter region in sporadic breast cancer[J].Jpn J Cancer Res,2000;91:519-26.
46 Catteau A,Harris WH,Xu CF.Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer:correlation with disease characteristics.characteristics.Oncogene,1999,18(11):1957-65.
47 俞鸣,郝希山,郝继辉等.散发性卵巢上皮性癌BRCA1基因表达的研究[J].中国癌症杂志,2003,13(2):153-158.
48 荆建红,史惠蓉.BRCA1蛋白在散发性卵巢癌组织中的表达[J].中国误诊学杂志,2004,4(8):1182-1193.
49 许燕云,刘标,唐慰萍,等.散发性乳腺癌中BRCA1和cyclin B1的表达[J].Clin Exp Pathol 2004,20(3):273-276.
50 Thompson ME,Jenson RA,Obermiller PS,et al.Decreased expression of BRCA1accelerates growth and is often present during sporadic breast cancer progression[J].Nat Genet,1998,9(4):444-450
51 Pual A.Russell,Paul D.P.Pharoah,Karen De Foy,Susan J.Ramus,Ian Symmonds,Snnie Wilson,et al.loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers.Int.J Cancer,2000,87:317-321
52 Aida H,Takakuwa K,Nagata H,et al.Clinical featuresof ovarian cancer in Japanese women with germ-line mutation of BRCA1.Clin Cancer Res.1998,Jan;4(1):235-240.
53 Boyod J,Sonoda Y,Federici MG,et al.Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.JAMA.2000;283(17):2260-2265.
54 Johannsson oT,Ranstam J,Borg A,et al.Survival of BRCA1 breast and ovarian cancer patients:a population-based study from southern Sweden.J Clin Oncol.1998;16:397-404.
55 Ronald Zweemer,Rene H.M.Verheijen,Jan-Willem W.Coebergh-Ian J.Jacobs,Paul J van Diest,Johan J.P Gille,et al.Suvival analysis in familial ovarian cancer,a case control study.European Journal of Obstetric and Gynecology and Reproductive Biology,2001,98:219-223
56 Werness,Bruce A.;Ramus,Susan J.;DiCioccio,Richard A.;Whittemore,Alice S.;Garlinghouse-Jones,Kim;Oakley-Girvan,Ingrid;et al.Histopathology,FIGO Stage,and BRCA Mutation Status of Ovarian Cancers from the Gilda Radner Familial Ovarian Cancer Registry.International J of gynecological Pathology,2004,23(1):29-34
57 Piver MS.Hereditary ovarian cancer.Lessons from the first twenty years of the Gilda Radner Familial Ovarian Cancer Registry。Gynecol Oncol。2002,85:9-17
58 沈铿,郎景和,黄荣丽,等.遗传性卵巢癌综合症的诊断和治疗对策.中华妇产科杂志,1996,3l(12):732-735
59 WenXin Zhang,Feng Lou,Jean J Lu.,Arimine Baltayan,Michael F.Press,Zuo-Feng Zhang,Malcolm C.Pike.Reduction of BRCAI Expression in Sporadic Ovarian Cancer.Gyneclolgy Ontology,2000,76:294-300
60 荆建红,史惠蓉。BRCA1蛋白在散发性卵巢癌组织中的表达[J].中国误诊学杂志,2004,4(8):1182-1184.
61 俞鸣,郝继辉,焦振山,等。卵巢上皮性癌BRCA1和p53基因表达的临床意义及相互关系研究[J].中国肿瘤临床,2005,32(1):18-20.
2 Thomas JE,Smith M,Wonkinson JL,et aI.Induction of phosphorylation on BRCA1 during the cell cycle and after DNA damage.Cell growth Diff,1999,8:801-809.
3 Yarden RI,Brody LC.BRCA1 interacts with components of the histone complex.Proc Natl Acad,2001,96(9);4983-4988.
4 Zhang H.,Somasundaram,K.,Peng Y.,et al.BRCA1 physically associates with p53and stimulates it stranscriptional activity.Oncogene,2000,16(13):1713-1721
5 Bork P,Hofmann K,Bucher P,et al.A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins.FASEB J,1999,11(1):68-76.
6 Shao N,Chai YL,Shyam E,et al.Induction of apoptosis by the tumor suppressor protein BRCAI.Oncogene,1996,13(1):1-7。
7 Lynch HT,Watson P,Bewtra C.Hereditary ovarian cancer:hereterogenerty in age at diagnosis.Cancer.1991;67:1460.
8 沈铿,郎景和,黄荣丽,等.遗传性卵巢癌综合症的诊断和治疗对策.中华妇产科杂志,1996,31(12):732-735
9 Pual A.Russell,Paul D.P.Pharoah,Karen De Foy,et al.Frequent loss of BRCAI mRNA and protein expression in sporadic ovarian cancers.Int.J Cancer,2000,87:317-321.
10 Khoo US,Chan KY,Cheung AN,et al.2002.Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer:a founder mutation of BRCA1 identified in the Chinese population.Hum Murat,2002,19:307-308.
11 Pual A.Russell,Paul D.P.Pharoah,Karen De Foy,et al.Frequent loss of BRCA1mRNA and protein expression in sporadic ovarian cancers.Int.J Cancer,2000,87:317-321.
12 乐杰主编.妇产科学.人民卫生出版社,北京,第五版,1998.
13 Hall JM,Lee MK,Newman B,et al.Science,1990,250:1684-1689
14 Miki,Y.;Swensen,J.;Shattuck-Eidens,D.;Futreal,P.A.;Harshman,K.;Tavtigian,S.;Liu,Q.;Cochran,C.;Bennett,L.M.;Ding,W.;Bell,R.;Rosenthal,J.;and 33 others:A strong candidate for the breast and ovarian cancer susceptibility gene BRCA 1.Science,1 994,266:66.
15 Patrcia S.Granin exceptions in breast cancer? Nature Genet.1999:12:223-30.
16 Chen C,Chen C,Riley CJ,et al.Aberrant subcellular localization of BRCA1 in breast cancer.Science.1998;270(5233-5238):789-791.
17 JhamwarUM.BRCA1 in cancer cycle and genomic stability[J].Front Biosci,2003, 8:S1107-S1110.
18 FitzGerald MG MacDonaldDJ,KrainerM,et al。Germ-line BRCA1 mutations in Jewish and non- Jewish women with early-onset breast cancer[J].New Engl L Med,1996,334(3):143-149。
19 Peng-Hui Wang,Wen-Yann Shyong,Ywan Feng Li,Hsein-Hsiung Lee,Wen-Ying Tsai,Hsiang-Tai Chao,et al.BRCA 1 Mutations in Taiwanese with Epithelial Ovarian Carcinoma and Sporadic Primary Serous Peritoneal Carcinoma.Japanese Journal of Clinical Oncology,2000,30:343-348.
20 俞鸣,郝继辉,郝希山,焦振山,史玉荣.卵巢癌患者BRCA1基因突变及临床意义.中华妇产科杂志,2003,38(4):251
21 Russell PA,Pharoah PDD,Foy KD,et al。Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers。Int J Cancer,2000,87(3):317-321
22 Chen,Y;Farmer,A.A.;Chen,C.-F.;Jones,D.C.:Chen,P.-L.;Lee,W.-H.:BRCA1is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner.Cancer Res.56:3168-3172,2001.
23 Pual A.Russell,Paul D.P.Pharoah,Karen De Foy,Susan J.Ramus,Ian Symmonds,Snnie Wilson,et al.loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers.Int.J Cancer,2000,87:317-321
24 WenXin Zhang,Feng Lou,Jean J Lu.,Arimine Baltayan,Michael F.Press,Zuo-Feng Zhang,Malcolm C.Pike.Reduction of BRCAI Expression in Sporadic Ovarian Cancer.Gyneclolgy Oncology,2000,76:294-300
25 Thompson ME,Jenson RA,Obermiller PS,et al.Decreased expression of BRCA1accelerates growth and is often present during sporadic breast cancer progression[J].Nat Genet,2002,9(4):444-450
26 Tanimoto H,Underwood LJ,Shigemasa K,Parmley TH.The matrix metalloprotease pump-1(MMP-7,Matrilysin):A candidate/target for ovarian cancer detection and treatment.Tumor Biol,1999,20(2):88-98
27 Scholzen T,Gerdes J,The Ki-67 protein:from the known and the unknown[J].J Cell P hysiol,2000,182:311-322.
28 Suo Z,Karbovo E,Trope CG,et al.Papillary serous carcinoma of the ovary:an ultrastructural and immunohistochemical study[J].Obstet Gynecol,2002,100(2):281-287.
29 Korkolopoulou P,Vassilopoulos I,Konstantinidou A E,et al.The combined evaluation of p27 Kip1 and Ki-67 expressio provides independent information on overall survival of ovarian carcinoma patients[J].Gynecol Ontol,2002,85(3):404-414
30 周虹,杨竹,蔡汉钟等.Ki-67抗原在卵巢肿瘤组织中的表达及意义[J}重庆医学,2005,34(2):252-253.
31 罗军.应用组织芯片技术分析卵巢癌组织中Ki-67的表达.实用癌症杂志.2003,18(3): 263-266
32 Itamochi H, Kigawa J, Sugiyama T, et al. Low proliferation activity may be associated with chemoresi stance in clear cell carcinoma of the ovary [J]. Obstet Gynecol, 2002,100 (2):281-287.
33 Munstedt K, von Georgi R, Franke FE, et al. Correlation between MIB1 determined tumor growth fraction and incident of tumor recurrence in early ovarian carcinomas[J]. Cancer Invest, 2004, 22 (2):185—194.
34 Costa MJ, Walls J, Ames P, et al .Transformation in recurrent ovarian granulosa cell tumors: Ki67 (MIB-1) and p53 immunohistochemi-stry demonstrates a possible molecular basis for the poor histopathologic prediction of clinical behavior[J]. Hum Pathol, 1996, 27 (3):274-81.
35 Nocito A , Bubendorf L , Tinner EM , et al . Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade (J ) . J Pat hol ,2001 ,194(3) :349.
36 Camp RL , Charet te LA , Rimm DL , et al . Validation of tissue microarray technology in breast carcinoma (J ) . Lab Invest ,2000 ,80(12) :1943.
37 Moch H , Schrami P , Bubendorf L , et al . High2t hroughput tissue microarray analysis to evaluate genes uncovered by cDNA microarray screening in renal carcinoma (J ) .Am J Pat hol ,1999 ,154(4) :981.
1 Hall JM, Lee MK, Newman B, et al. Science, 1990, 250:1684-1689
2 Narod SA, Feunteun J, Lynch H 1, et al. Familial breast-ovarian cancer locus on chromosome 17ql2-q23. Lancet, 1991, 338(8759):82-83.
3 Miki, Y. ; Swensen, J. ; Shattuck-Eidens, D. ; Futreal, P. A. ; Harshman, K. ; Tavtigian,S. ; Liu, Q. ; Cochran, C. ; Bennett, L. M. ; Ding, W. ; Bell, R. ; Rosenthal, J. ; and 33 others:A strong candidate for the breast ard ovarian cancer susceptibility gene BRCA 1. Science, 1 994,266:66.
4 Lynch HT, Watson P, Bewtra C. Hereditary ovarian cancer: hereterogenerty in age at diagnosis. Cancer. 1991;67:1460.
5 Garvin AM, AttenhoferHaner M, Scott RJ. BRCA1 and BRCA2 analysis in 86 early onset breast/ovarian cancer patients. J Med Genet, 1997,34:990-995.
6 Patrcia S. Granin exceptions in breast cancer? Nature Genet. 1999; 12:223-30.
7 Chen C, Chen C, RileyCJ, et al. Aberrant subcellular localization of BRCA1 in breast cancer. Science. 2000;270(5233-5238):789-791.
8 Feunteun J. Breast cancer and genetic instability: the mo lecules behind the scenes (J) . Mo lecularM edicine Today, 1998, 6: 263
9 Hakem R et al.Cell, 1996; 85: 1009
10 Jernstrem H et al. Eur J Cancer, 1998; 34: 368
11 Scully R, Chen J, Ochs RL, et al。 Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage [J].Cell, 1997, 90 (3) :425-435
12 Yan Y, et al. [ J ] . J Biol Chem , 2002 , 277(36):33422-33430.
13 Harkin PD , et al. [ J ] . Cell , 1999 , 97 : 575-586.
14 Xu X, et al. [J ] . Nat Genet , 2001 ,28(3) :266-271.
15 Harkin PD , et al. [ J ] . Cell , 1999 , 97 : 575-586.
16 Thangaraju M, et al. [J ] . J Biol Chem , 2000 ,275 (43) :33487-33496.
17 Clarke LH. [J ] . Cancer Res , 2000 ,60 : 4993-5001.
18 Fan S , et al. [J ] . Science , 1999 , 284 (5418) :1354-1356.
19 Rattenborg T, et al. [J ] . Breast Cancer Res ,2002 ,4 : R12.
20 Chen JJ, Silver D, Cantor S, et alo BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway [J]。 Cancer Res, 1999, 59 (7Suppl) : 1752s-1756s
21 Zhong Q, Chen CF, Li S, et alo Association of BRCA1 with the hRad50-h Mrell-p95 complex and the DNA damage response [J] 。 Science, 1999, 285 (5428) : 747-750
22 Wang Y, Cortez D, Yazdi P, et al。 BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures [J] 。Genes Dev, 2000, 14 (8) : 927-939
23 MacLachlan TK, Takimoto R, El-DeiryWS. BRCA1 directs a selective p53 - dependent transcriptional response towards growth arrest and DNA repair targets[J].Mol Cell Biol,2002,22(12):4280-42851
24 Somasundaram K,Zhang H,Zeng YX,et al.Arrest of cell cycle by the tumor-supp ressor BRCA1 requires the CDK-inhibitor p21WAF1/Cip l[J].Nature,2002,389(6647):187-190.
25 Fan W,J in S,Tong T,et al.BRCA1 regulates GADD45 through its interactions with the OCT21 and CAAT motifs[J].J Biol Chem,2002,277(10):8061-8067.
26 Williamson EA,Dadmanesh F,Koeffler HP.BRCA1 transactivates the cyclin-dependent kinase inhibitor p27(Kipl)[J].Oncogene,2002,21(20):3199-3204.
27 Fan S,Wang J,Yuan R,et al.BRCA1 inhibition of estrogen receptor signaling in transfected cells[J].Science,1999,284(5418):1354-1359.
28 Zheng L,Annab LA,Afshari CA,et al.BRCA1 mediates ligand- independent transcrip tional rep ression of the estrogen receptor[J].Proc Natl Acad Sci USA,2001,98(17):9587-9593。
29 Rosen EM,Fan S,Pestell RG,et al.BRCA1 in hormone-responsive cancers[J].Trends EndocrinolMetab,2003,14(8):378.
30 Wang Q,Zhang H,Kajino K,et al.BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells[J].Oncogene,1998,17(15):1939-19451
31 Schuyer M,Bern EM,Is TP53 dysfunction required for BRCA1-associated carcinogenesis[J]Mol Cell Endorcrinol,1999,155(1-2):143
32 Fitzgerald MG MacDonald DJ,Krainer M,et al。Germ-line BRCA1 mutations in Jewish and non- Jewish women with early-onset breast cancer[J].New Engl L Med,1996,334(3):143-149。
33 Inoue R,Fukutomi T,Ushijima T,et al。Germline mutation of BRCA1 in Japanese breast cancer families[J].Cancer Res,1998,55(16):3521-3524.
34 丁晓曼,郎景和.BRCA1基因在早发性乳腺癌中的突变[J].中华医学杂志,2000,80(2):111-113.
35 赖春宁,江泽飞,宋三泰,等186例乳腺癌患者BRCA1基因突变检测[J]5中华肿瘤杂志,2001,23(6):483-485.
36 Peng-Hui Wang,Wen-Yann Shyong,Ywan Feng Li,Hsein-Hsiung Lee,Wen-Ying Tsai,Hsiang-Tai Chao,et al.BRCA 1 Mutations in Taiwanese with Epithelial Ovarian Carcinoma and Sporadic Primary Serous Peritoneal Carcinoma.Japanese Journal of Clinical Oncology,2000,30:343-348.
37 俞鸣,郝继辉,郝希山,焦振山,史玉荣.卵巢癌患者BRCA1基因突变及临床意义.中华妇产科杂志,2003,38(4):251
38 Chen,Y;Farmer,A.A.;Chen,C.-F.;Jones,D.C.;Chen,P.-L.;Lee,W.-H.:BRCA1is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner.Cancer Res.56:3168-3172,2001.
39 曾益新.肿瘤学[M].第2版,北京:人民卫生出版社,1999,69.
40 Hiroaki F,Manabu Y,Zhu XG,et al.Frequent genetic heterogeneity in the clonal evolution of gynecological carcinosarcoma and its influence on phenotypic diversity[J].Cancer Res,2000,60:114
41 Manderson EN,Presneau N,Provencher D,et al.Comparative analysis of loss of heterozygosity of specific chromosome 3,13,17,and X loci and TP53 mutations in human epithelial ovarian cancer[J].Mol Carcinog,2002,34(2):78
42 Bird AP.CpG-rich-island,and the function of DNAmethylation[J].Nature,1996;321:209-13.
43 EstellerM,Corn PG,Baylin SB,et al.A gene hypermethylation profile of human cancer [J].Cancer Res,2001;61:3225-9.
44 Carmen J,Costa I,Martins MC,et al.Detection of gene promoter hypermethy-lation in fine needle washings from breast lesions[J].Clin Cancer Res,2003;9:3413-7.
45 Showa Y,Oyama T,Nakajima T et al.BRCA1 expression status in relation to DNA methylation of BRCA1 promoter region in sporadic breast cancer[J].Jpn J Cancer Res,2000;91:519-26.
46 Catteau A,Harris WH,Xu CF.Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer:correlation with disease characteristics.characteristics.Oncogene,1999,18(11):1957-65.
47 俞鸣,郝希山,郝继辉等.散发性卵巢上皮性癌BRCA1基因表达的研究[J].中国癌症杂志,2003,13(2):153-158.
48 荆建红,史惠蓉.BRCA1蛋白在散发性卵巢癌组织中的表达[J].中国误诊学杂志,2004,4(8):1182-1193.
49 许燕云,刘标,唐慰萍,等.散发性乳腺癌中BRCA1和cyclin B1的表达[J].Clin Exp Pathol 2004,20(3):273-276.
50 Thompson ME,Jenson RA,Obermiller PS,et al.Decreased expression of BRCA1accelerates growth and is often present during sporadic breast cancer progression[J].Nat Genet,1998,9(4):444-450
51 Pual A.Russell,Paul D.P.Pharoah,Karen De Foy,Susan J.Ramus,Ian Symmonds,Snnie Wilson,et al.loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers.Int.J Cancer,2000,87:317-321
52 Aida H,Takakuwa K,Nagata H,et al.Clinical featuresof ovarian cancer in Japanese women with germ-line mutation of BRCA1.Clin Cancer Res.1998,Jan;4(1):235-240.
53 Boyod J,Sonoda Y,Federici MG,et al.Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.JAMA.2000;283(17):2260-2265.
54 Johannsson oT,Ranstam J,Borg A,et al.Survival of BRCA1 breast and ovarian cancer patients:a population-based study from southern Sweden.J Clin Oncol.1998;16:397-404.
55 Ronald Zweemer,Rene H.M.Verheijen,Jan-Willem W.Coebergh-Ian J.Jacobs,Paul J van Diest,Johan J.P Gille,et al.Suvival analysis in familial ovarian cancer,a case control study.European Journal of Obstetric and Gynecology and Reproductive Biology,2001,98:219-223
56 Werness,Bruce A.;Ramus,Susan J.;DiCioccio,Richard A.;Whittemore,Alice S.;Garlinghouse-Jones,Kim;Oakley-Girvan,Ingrid;et al.Histopathology,FIGO Stage,and BRCA Mutation Status of Ovarian Cancers from the Gilda Radner Familial Ovarian Cancer Registry.International J of gynecological Pathology,2004,23(1):29-34
57 Piver MS.Hereditary ovarian cancer.Lessons from the first twenty years of the Gilda Radner Familial Ovarian Cancer Registry。Gynecol Oncol。2002,85:9-17
58 沈铿,郎景和,黄荣丽,等.遗传性卵巢癌综合症的诊断和治疗对策.中华妇产科杂志,1996,3l(12):732-735
59 WenXin Zhang,Feng Lou,Jean J Lu.,Arimine Baltayan,Michael F.Press,Zuo-Feng Zhang,Malcolm C.Pike.Reduction of BRCAI Expression in Sporadic Ovarian Cancer.Gyneclolgy Ontology,2000,76:294-300
60 荆建红,史惠蓉。BRCA1蛋白在散发性卵巢癌组织中的表达[J].中国误诊学杂志,2004,4(8):1182-1184.
61 俞鸣,郝继辉,焦振山,等。卵巢上皮性癌BRCA1和p53基因表达的临床意义及相互关系研究[J].中国肿瘤临床,2005,32(1):18-20.