Volume 44, Issue 3 , Pages 218-231, September 2005
Genetic Changes in Ovarian Cancer
Article Outline
Summary
Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Chemoresistance may be multifactorial and related to multiple mechanisms, such as alterations in drug transport, changes in cellular proteins involved in detoxification, altered drug target, changes in DNA repair mechanisms, increases in drug damage tolerance, and genetic changes. Genetic changes appear to be associated directly with the loss of chemosensitivity in ovarian cancer. In this review, we detail the possible genetic changes that occur in ovarian cancer, including activation of specific oncogenes, inactivation of tumor suppressor genes, and downregulation of metastasis suppressor genes.
Key Words: metastasis suppressor gene , oncogene , ovarian cancer , tumor suppressor gene
No full text is available. To read the body of this article, please view the PDF online.
References
- . Treatment of gynecologic cancer: the US experience . Tumori . 1999;85:S5–11
- . Oncogenes . In: Bast RC , Kufe DW , Pollock RE , Weischselbaum RR , Holland JF , Frei E editor. Cancer Medicine . Ontario: BC Decker Inc; 2000;p. 56–66
- A genetically defined model for human ovarian cancer . Cancer Res . 2004;64:1655–1663
- . Ras genes . Annu Rev Biochem . 1987;56:779–827
- . Biochip for K-ras mutation screening in ovarian cancer . Clin Chem . 2005;51:784–787
- . Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes . Cell . 1988;53:549–554
- Prevalence of ras gene mutations in human colorectal cancers . Nature . 1987;327:293–297
- . Detection of high incidence of K-ras oncogenes during human colon tumorigenesis . Nature . 1987;327:298–303
- . Preferential and novel activation of H-ras in human bladder carcinomas . Oncogene Res . 1988;3:77–86
- Mutations in N-ras predominate in acute myeloid leukemia . Blood . 1987;69:1237–1241
- Lysophosphatidic acid stimulates ovarian cancer cell migration via a ras-MEK kinase 1 pathway . Cancer Res . 2004;64:4209–4217
- . Origins and molecular pathology of ovarian cancer . Mod Pathol . 2005;18:S19–S32
- K-ras alterations in Danish ovarian tumour patients. From the Danish “Malova” ovarian cancer study . Gynecol Oncol . 2003;89:31–36
- Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma . J Natl Cancer Inst . 2003;95:484–486
- Diverse tumorigenic pathways in ovarian serous carcinoma . Am J Pathol . 2002;160:1223–1228
- . Inactivation of the mitogen-activated protein kinase pathway as a potential target-based therapy in ovarian serous tumors with KRAS or BRAF mutations . Cancer Res . 2005;65:1994–2000
- Characterization of active mitogen-activated protein kinase in ovarian serous carcinomas . Clin Cancer Res . 2004;10:6432–6436
- . Expression status and mutational analysis of the ras and B-raf genes in ovarian granulosa cell and epithelial tumors . Gynecol Oncol . 2004;95:603–609
- K-ras mutation may promote carcinogenesis of endometriosis leading to ovarian clear cell carcinoma . Med Electron Microsc . 2004;37:188–192
- Oncogenic potential of c-erbB-2 and its association with c-K-ras in premalignant and malignant lesions of the human uterine endometrium . Tumour Biol . 2001;22:299–309
- . Malignant transformation of endometriosis and genetic alterations of K-ras and microsatellite instability . Int J Gynaecol Obstet . 2004;86:371–376
- . Silencing of H-ras gene expression by retrovirus-mediated siRNA decreases transformation efficiency and tumor growth in a model of human ovarian cancer . Oncogene . 2003;22:5694–5701
- . HER-2/neu signal transduction in human breast and ovarian cancer . Stem Cells . 1997;15:1–8
- . Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts . Nature . 1981;290:261–262
- Studies of the HER- 2/neu proto-oncogene in human breast and ovarian cancer . Science . 1989;244:707–712
- . HER-2/neu oncogene amplification in stage I and stage III ovarian papillary serous carcinoma . Exp Mol Pathol . 1999;66:165–169
- Contribution of c-erbB-2 and topoisomerase II alpha to chemoresistance in ovarian cancer . Cancer Res . 1999;59:3206–3214
- . Overexpression of the oncogene c-erbB-2 (HER2/neu) and response to chemotherapy in patients with ovarian cancer . Int J Gynecol Pathol . 1998;17:61–65
- . Prognostic significance of c-erB-2 mRNA in ovarian carcinoma . Gynecol Oncol . 1996;62:268–277
- . Overexpression of the oncogene c-erbB- 2 (HER2/neu) in ovarian cancer: a new prognostic factor . Eur J Obstet Gynecol Reprod Biol . 1997;71:173–179
- . The effect of HER-2/neu overexpression on chemo-therapeutic drug sensitivity in human breast and ovarian cancer cells . Oncogene . 1997;15:537–547
- . Enhanced chemoresistance by elevation of p185neu level in HER2/neu-transfected human lung cancer cells . J Natl Cancer Inst . 1995;87:682–684
- . Overexpression of c-erbB-2/neu in breast cancer cells confers increased resistance to Taxol via mdr-1-independent mechanisms . Oncogene . 1996;13:1359–1365
- . The prognostic and predictive value of immunohistochemically detected HER-2/neu overexpression in 361 patients with ovarian cancer: a multicenter study . Gynecol Oncol . 2004;95:89–94
- . c-Cbl associates directly with the C-terminal tail of the receptor for the macrophage colony-stimulating factor, c-Fms, and down-modulates this receptor but not the viral oncogene v-Fms . J Biol Chem . 2002;277:14635–14640
- . A point mutation in the extracellular domain of the human CSF-1 receptor (c-fms proto-oncogene product) activates its transforming potential . Cell . 1988;55:979–988
- . Activation of the feline c-fms proto-oncogene: multiple alterations are required to generate a fully transformed phenotype . Cell . 1988;55:965–977
- Expression of c-fms proto-oncogene product by ovarian cancer cell lines with effects of macrophage colony-stimulating factor on proliferation . Oncology . 1996;53:99–103
- . Modulation of c-fms proto-oncogene in an ovarian carcinoma cell line by a hammerhead ribozyme . Br J Cancer . 1997;76:977–982
- Amplification and overexpression of the L-MYC proto-oncogene in ovarian carcinomas . Am J Pathol . 2003;162:1603–1610
- . HER2 signaling enhances 5'UTR-mediated translation of c-Myc mRNA . J Cell Physiol . 2004;200:82–88
- . Role of p53 in HER2-induced proliferation or apoptosis . J Biol Chem . 2001;276:12449–12453
- . c-myc over-expression in human primary ovarian tumours: its relevance to tumour progression . Int J Cancer . 1992;50:828–833
- Expression of the c-myc gene as a predictor of chemotherapy response and a prognostic factor in patients with ovarian cancer . Cancer Sci . 2004;95:418–423
- . The quest for a tumor suppressor gene phenotype . Curr Mol Med . 2003;3:605–629
- . Redefining tumour suppressor genes: exceptions to the two-hit hypothesis . Cell Mol Life Sci . 2003;60:2147–2163
- . Mutational spectrum of p53 mutations in primary breast and ovarian tumors . Crit Rev Oncol Hematol . 2004;52:103–116
- . Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis . Cancer Res . 1994;54:4855–4878
- . p53 gene mutation: software and database . Nucl Acids Res . 1998;26:200–204
- DNA sequence analysis of exons 2 through 11 and immunohistochemical staining are required to detect all known p53 alterations in human malignancies . Oncogene . 1996;13:1971–1981
- p53 expression, DNA ploidy and mitotic index as prognostic factors in patients with epithelial ovarian carcinoma . Tumori . 2004;90:600–606
- Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation . Am J Surg Pathol . 2005;29:218–224
- p53 mutation is infrequent in clear cell carcinoma of the ovary . Gynecol Oncol . 2001;80:189–193
- . Mutation and overexpression of p53 in early-stage epithelial ovarian cancer . Obstet Gynecol . 1993;81:643–650
- Overexpression and mutation of p53 in epithelial ovarian cancer . Cancer Res . 1991;51:2979–2984
- Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer . Clin Cancer Res . 2001;7:2984–2997
- . Apoptosis: a link between cancer genetics and chemotherapy . Cell . 2002;108:153–164
- p53 gene status and chemosensitivity in ovarian cancer . Hum Cell . 2001;14:165–171
- p53 alterations are predictive of chemoresistance and aggressiveness in ovarian carcinomas: a molecular and immunohistochemical study . Br J Cancer . 1997;75:230–235
- A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma . Cancer Res . 1996;56:689–693
- . Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy . Nat Med . 1995;1:1029–1034
- An I.T.M.O. group study on second-line treatment in advanced epithelial ovarian cancer: an attempt to identify clinical and biological factors determining prognosis . Eur J Cancer . 1995;31:2248–2254
- Breast cancer response to adjuvant chemotherapy in correlation with erbB2 and p53 expression . Anticancer Res . 1994;14:2773–2778
- . Therapy effect of either paclitaxel or cyclophosphamide combination treatment in patients with epithelial ovarian cancer and relation to TP53 gene status . Br J Cancer . 1998;78:375–381
- . Prolonged wild-type p53 protein accumulation and cisplatin resistance . Biochem Biophys Res Commun . 2001;283:732–737
- Development and characterization of five cell models for chemoresistance studies of human ovarian carcinoma . Int J Mol Med . 2004;14:257–264
- High effectiveness of platinum(IV) complex with adamantylamine in overcoming resistance to cisplatin and suppressing proliferation of ovarian cancer cells in vitro . Biochem Pharmacol . 2005;69:373–383
- . p53 is a determinant of Xiap/Akt-mediated chemoresistance in human ovarian cancer cells . Cancer Res . 2003;63:7081–7088
- Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer . Am J Hum Genet . 2001;68:700–710
- . Improved survival in women with BRCA-associated ovarian carcinoma . Cancer . 2003;97:2187–2195
- . Hereditary ovarian cancer in Ashkenazi Jews . Fam Cancer . 2004;3:259–264
- . BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair . Nat Genet . 2002;32:180–184
- BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure . Science . 2002;297:1837–1848
- Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells . Mol Cell . 1999;3:389–395
- . Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression . Nat Genet . 1995;9:444–450
- The tumor suppressor gene BRCA1 is required for embryonic cellular proliferation in the mouse . Cell . 1996;85:1009–1023
- Clinicopathologic features of BRCA-linked and sporadic ovarian cancer . JAMA . 2000;283:2260–2265
- Effect of BRCA mutations on the length of survival in epithelial ovarian tumors . J Clin Oncol . 2002;20:463–466
- Clinical and pathological features of ovarian cancer in women with germline mutations of BRCA1 . N Engl J Med . 1996;335:1413–1416
- Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1 . Clin Cancer Res . 1998;4:235–240
- . Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden . J Clin Oncol . 1998;16:397–404
- . Survival in familial, BRCA1-associated, and BRCA2- associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group . Cancer Res . 1999;59:868–871
- Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers . Cancer Res . 1998;58:3193–3196
- . Altered expression and loss of heterozygosity of the LOT1 gene in ovarian cancer . Gynecol Oncol . 2004;95:449–455
- . Loss of heterozygosity on the long arm of chromosome 6 in breast cancer: possibly four regions of deletion . Clin Cancer Res . 1996;2:1601–1606
- . Genome-wide allelotyping of a new in vitro model system reveals early events in breast cancer progression . Cancer Res . 2002;62:5980–5987
- Chromosome 6 abnormalities in ovarian surface epithelial tumors of borderline malignancy suggest a genetic continuum in the progression model of ovarian neoplasms . Clin Cancer Res . 2001;7:3404–3409
- Identification of a gene containing zinc-finger motifs based on lost expression in malignantly transformed rat ovarian surface epithelial cells . Cancer Res . 1997;57:2029–2034
- . Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain . EMBO J . 1997;16:2814–2825
- . Transcriptional activation capacity of the novel PLAG family of zinc finger proteins . J Biol Chem . 1998;273:23026–23032
- Identification of a zinc-finger gene at 6q25: a chromosomal region implicated in development of many solid tumors . Oncogene . 1997;14:1973–1979
- . LOT1 is a growth suppressor gene down-regulated by the epidermal growth factor receptor ligands and encodes a nuclear zinc-finger protein . Oncogene . 1999;18:6477–6487
- . LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24–25, is epigenetically regulated in cancer . J Biol Chem . 2003;278:6041–6049
- Loss of expression of a new member of the DNAJ protein family confers resistance to chemotherapeutic agents used in the treatment of ovarian cancer . Cancer Res . 2001;61:4258–4265
- . Cell type-specific methylation of an intronic CpG island controls expression of the MCJ gene . Carcinogenesis . 2004;25:693–701
- . Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site . J Urol . 2003;169:1122–1133
- . Metastasis-suppressor genes: a review and perspective on an emerging field . J Natl Cancer Inst . 2001;92:1717–1730
- . Genetic factors and suppression of metastatic ability of prostatic cancer . Cancer Res . 1991;51:3788–3792
- Localization of metastasis suppressor gene(s) for prostatic cancer to the short arm of human chromosome 11 . Cancer Res . 1992;52:3486–3490
- KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2 . Science . 1995;268:884–886
- . Frequent downregulation of the KAI1 (CD82) metastasis suppressor protein in human cancer cell lines . Oncogene . 1998;16:3143–3149
- Down-regulation of the KAI1 metastasis suppressor gene during the progression of human prostatic cancer infrequently involves gene mutation or allelic loss . Cancer Res . 1996;56:4387–4390
- Expression of the KAI1 protein in benign prostatic hyperplasia and prostate cancer . Am J Pathol . 1996;149:1435–1440
- . Loss of expression and altered localization of KAI1 and CD9 protein are associated with epithelial ovarian cancer progression . Gynecol Oncol . 2002;86:69–78
- . Frequent down-regulation and lack of mutation of the KAI1 metastasis suppressor gene in epithelial ovarian carcinoma . Gynecol Oncol . 2000;78:10–15
- Suppressive role of the metastasis-related nm23-H1 gene in human ovarian carcinomas: association of high messenger RNA expression with lack of lymph node metastasis . Cancer Res . 1995;55:2645–2650
- Expression of the antimetastatic gene nm23 in human breast cancer: an association with good prognosis . J Natl Cancer Inst . 1991;83:281–285
- Nm23 “anti-metastatic” gene product expression in colorectal carcinoma . J Pathol . 1994;172:261–266
- Level of nm23 messenger RNA in metastatic malignant melanoma: inverse correlation to disease progression . Cancer Res . 1992;52:6088–6091
- Immunohistochemical analysis of expression of nm23H1/nucleoside diphosphate kinase in human thyroid carcinomas: lack of correlation between its expression and lymph node metastasis . Thyroid . 1994;3:105–109
- Immunohisto-chemical analysis of nm23 gene product/NDP kinase expression in pulmonary adenocarcinoma: lack of prognostic value . Br J Cancer . 1992;66:533–536
- Nm23 in ovarian cancer: correlation with clinical outcome and other clinico-pathological and biochemical prognostic parameters . J Clin Oncol . 1996;14:334–342
- . Nm23 expression in tissue sections and tumor effusion cells of ovarian neoplasms . Int J Cancer . 1996;69:415–419
- Nm23 expression in advanced and borderline ovarian carcinoma . Anticancer Res . 1996;16:1197–1202
- . Prognostic role of nm23 gene expression in patients with ovarian cancer . Am J Clin Oncol . 2002;25:164–167
- . Mitogen-activated protein kinase kinase 4 (MKK4) . Int J Biochem Cell Biol . 2000;32:581–587
- . Mitogen-activated protein kinase kinase 4/stress activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17 . Cancer Res . 1999;59:5483–5487
- Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers . Cancer Res . 2001;61:2833–2837
- Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma . Cancer Res . 2002;62:6717–6723
PII: S1028-4559(09)60144-3
doi:10.1016/S1028-4559(09)60144-3
© 2005 Taiwan Association of Obstetric & Gynecology. Published by Elsevier Inc. All rights reserved.
Volume 44, Issue 3 , Pages 218-231, September 2005
