Skip to main content
×
Home
    • Aa
    • Aa

Critical molecular abnormalities in high-grade serous carcinoma of the ovary

  • Martin Köbel (a1) (a2), David Huntsman (a1) and C. Blake Gilks (a1)
Abstract

Ovarian carcinomas show more morphological heterogeneity than adenocarcinomas of any other body site. It has recently become clear that the morphologically defined subtypes of ovarian carcinoma are distinct diseases, with different risk factors, molecular events during oncogenesis, likelihood of spread, responses to chemotherapy, and outcomes. This review focuses on molecular abnormalities (in genes expressing BRCA1/2, TP53 and RB1/CCND1/CDKN2A/E2F) found in high-grade serous carcinomas of the ovary, which account for most ovarian cancer deaths. These highly aggressive but chemosensitive tumours are associated with perturbation of molecular pathways leading to genomic instability and extreme mutability and present unique challenges in oncological research and practice.

Copyright
Corresponding author
*Corresponding author: C. Blake Gilks, Department of Pathology, Room 1207 1st floor JPPN, Vancouver General Hospital, 855 West 12th Ave, Vancouver, BC, Canada, V5Z 1M9. Tel.: +1 (604) 875 4901; Fax: +1 (604) 875 4797; E-mail: Blake.Gilks@vch.ca
References
Hide All
1Tavasolli F.A. and Devilee P. (2003) World Health Organization Classification of Tumours. Tumours of the Breast and the Femal Genital Organs. IARC Press, WHO.
2Auersperg N. et al. (2001) Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev 22, 255-288
3Crum C.P. et al. (2007) Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clin Med Res 5, 35-44
4Gilks C.B. et al. (2008) Tumor cell type can reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum Pathol (in press)
5Seidman J.D. et al. (2004) The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol 23, 41-44
6Soslow R.A. (2008) Histologic subtypes of ovarian carcinoma: an overview. Int J Gynecol Pathol 27, 161-74
7Takano M. et al. (2006) Clear cell carcinoma of the ovary: a retrospective multicentre experience of 254 patients with complete surgical staging. Br J Cancer 94, 1369-1374
8duBois A. et al. (2003) A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95, 1320-1329
9Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. (2002) Lancet 360, 505-515
10Shih I. and Kurman R.J. (2004) Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 164, 1511-1518
11Han G. et al. (2008) Interobserver variation in diagnosing mixed ovarian epithelial carcinoma with a clear cell component. Am J Surg Pathol 32, 955-964
12Köbel M. et al. (2008) A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. Am J Surg Pathol (in press)
13Waldstrom M. and Grove A. (2005) Immunohistochemical expression of wilms tumor gene protein in different histologic subtypes of ovarian carcinomas. Arch Pathol Lab Med 129, 85-88
14Al Hussaini M. et al. (2004) WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma. Histopathology 44, 109-115
15Malpica A. et al. (2004) Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol 28, 496-504
16Malpica A. et al. (2007) Interobserver and intraobserver variability of a two-tier system for grading ovarian serous carcinoma. Am J Surg Pathol 31, 1168-1174
17Singer G. et al. (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95, 484-486
18Singer G. et al. (2005) 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 29, 218-224
19Crispens M.A. et al. (2002) Response and survival in patients with progressive or recurrent serous ovarian tumors of low malignant potential. Obstet Gynecol 99, 3-10
20Gershenson D.M. et al. (2006) Clinical behavior of stage II-IV low-grade serous carcinoma of the ovary. Obstet Gynecol 108, 361-368
21Kurman R.J. and Shih I. (2008) Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol 27, 151-160
22Gilks C.B. (2004) Subclassification of ovarian surface epithelial tumors based on correlation of histologic and molecular pathologic data. Int J Gynecol Pathol 23, 200-205
23Medeiros F. et al. (2006) The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 30, 230-236
24Kindelberger D.W. et al. (2007) Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 31, 161-169
25Salvador S. et al. (2008) Chromosomal instability in fallopian tube precursor lesions of serous carcinoma and frequent monoclonality of synchronous ovarian and fallopian tube mucosal serous carcinoma. Gynecol Oncol (in press)
26Salvador S. et al. (2008) The Fallopian Tube: Primary Site of Most Pelvic High-Grade Serous Carcinomas. Int J Gynecol Cancer (in press)
27Tutt A.N. et al. (2005) Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb Symp Quant Biol 70, 139-148
28Tutt A. et al. (2001) Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J 20, 4704-4716
29Modan B. et al. (2001) Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345, 235-240
30Moslehi R. et al. (2000) BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66, 1259-1272
31Risch H.A. et al. (2001) Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68, 700-710
32Hilton J.L. et al. (2002) Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst 94, 1396-1406
33Press J.Z. et al. (2008) Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 8, 17
34Shaw P.A. et al. (2002) Histopathologic features of genetically determined ovarian cancer. Int J Gynecol Pathol 21, 407-411
35Foster K.A. et al. (1996) Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res 56, 3622-3625
36Collins N. et al. (1997) Absence of methylation of CpG dinucleotides within the promoter of the breast cancer susceptibility gene BRCA2 in normal tissues and in breast and ovarian cancers. Br J Cancer 76, 1150-1156
37Brown L.A. et al. (2006) Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas. Gynecol Oncol 100, 264-270
38Raouf A. et al. (2005) Genomic instability of human mammary epithelial cells overexpressing a truncated form of EMSY. J Natl Cancer Inst 97, 1302-1306
39Boyd J. et al. (2000) Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 283, 2260-2265
40Ben David Y. et al. (2002) Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20, 463-466
41Quinn J.E. et al. (2007) BRCA1 mRNA Expression Levels Predict for Overall Survival in Ovarian Cancer after Chemotherapy. Clin Cancer Res 13, 7413-7420
42Bhattacharyya A. et al. (2000) The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 275, 23899-23903
43Narod S.A. and Boyd J. (2002) Current understanding of the epidemiology and clinical implications of BRCA1 and BRCA2 mutations for ovarian cancer. Curr Opin Obstet Gynecol 14, 19-26
44Farmer H. et al. (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917-921
45Sakai W. et al. (2008) Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116-1120
46Edwards S.L. et al. (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111-1115
47Swisher E.M. et al. (2008) Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res 68, 2581-2586
48Vogelstein B. and Kinzler K.W. (2004) Cancer genes and the pathways they control. Nat Med 10, 789-799
49Xing D. and Orsulic S. (2006) A mouse model for the molecular characterization of brca1-associated ovarian carcinoma. Cancer Res 66, 8949-8953
50Flesken-Nikitin A. et al. (2003) Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium. Cancer Res 63, 3459-3463
51Wu R. et al. (2007) Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways. Cancer Cell 11, 321-333
52Garcia A. et al. (2000) Loss of heterozygosity on chromosome 17q in epithelial ovarian tumors: association with carcinomas with serous differentiation. Int J Gynecol Pathol 19, 152-157
53Salani R. et al. (2008) Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance. Int J Gynecol Cancer 18, 487-491
54Havrilesky L. et al. (2003) Prognostic significance of p53 mutation and p53 overexpression in advanced epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 21, 3814-3825
55Moreno C.S. et al. (2007) Evidence that p53-Mediated Cell-Cycle-Arrest Inhibits Chemotherapeutic Treatment of Ovarian Carcinomas. PLoS ONE 2, e441
56Lavarino C. et al. (2000) p53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma. J Clin Oncol 18, 3936-3945
57Kandioler-Eckersberger D. et al. (2000) TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res 6, 50-56
58Crijns A.P. et al. (2003) Prognostic factors in ovarian cancer: current evidence and future prospects. In The ECCO 12 Educational Book of Eur J Cancer, pp. 127-145
59Lassus H. et al. (2003) Distinct subtypes of serous ovarian carcinoma identified by p53 determination. Gynecol Oncol 91, 504-512
60Singer G. et al. (2005) 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 29, 218-224
61Ichimura K. et al. (2000) Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res 60, 417-424
62Bonome T. et al. (2005) Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. Cancer Res 65, 10602-10612
63Gilks C.B. et al. (2005) Distinction between serous tumors of low malignant potential and serous carcinomas based on global mRNA expression profiling. Gynecol Oncol 96, 684-694
64Meinhold-Heerlein I. et al. (2005) Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential. Oncogene 24, 1053-1065
65Kommoss S. et al. (2007) Independent prognostic significance of cell cycle regulator proteins p16(INK4a) and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group. Br J Cancer 96, 306-313
66Schultz D.C. et al. (1995) Characterization of chromosome 9 in human ovarian neoplasia identifies frequent genetic imbalance on 9q and rare alterations involving 9p, including CDKN2. Cancer Res 55, 2150-2157
67Katsaros D. et al. (2004) Methylation of tumor suppressor gene p16 and prognosis of epithelial ovarian cancer. Gynecol Oncol 94, 685-692
68Armes J.E. et al. (2005) Abnormalities of the RB1 pathway in ovarian serous papillary carcinoma as determined by overexpression of the p16(INK4A) protein. Int J Gynecol Pathol 24, 363-368
69Bali A. et al. (2004) Cyclin D1, p53, and p21Waf1/Cip1 expression is predictive of poor clinical outcome in serous epithelial ovarian cancer. Clin Cancer Res 10, 5168-5177
70Kim T.M. et al. (1994) Loss of heterozygosity on chromosome 13 is common only in the biologically more aggressive subtypes of ovarian epithelial tumors and is associated with normal retinoblastoma gene expression. Cancer Res 54, 605-609
71Gorringe K.L. et al. (2007) High-resolution single nucleotide polymorphism array analysis of epithelial ovarian cancer reveals numerous microdeletions and amplifications. Clin Cancer Res 13, 4731-4739
72Harris S.L. and Levine A.J. (2005) The p53 pathway: positive and negative feedback loops. Oncogene 24, 2899-2908
73Nakayama K. et al. (2007) Amplicon profiles in ovarian serous carcinomas. Int J Cancer 120, 2613-2617
74Staebler A. et al. (2006) Chromosomal losses of regions on 5q and lack of high-level amplifications at 8q24 are associated with favorable prognosis for ovarian serous carcinoma. Genes Chromosomes Cancer 45, 905-917
75Pelengaris S. et al. (2002) c-MYC: more than just a matter of life and death. Nat Rev Cancer 2, 764-776
76Farley J. et al. (2003) Cyclin E expression is a significant predictor of survival in advanced, suboptimally debulked ovarian epithelial cancers: a Gynecologic Oncology Group study. Cancer Res 63, 1235-1241
77Gabriel B. et al. (2002) Molecular mechanisms in signal transduction: new targets for the therapy of gynecologic malignancies. Onkologie 25, 240-247
78Bookman M.A. et al. (2003) Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol 21, 283-290
79Riener E.K. et al. (2004) The prognostic and predictive value of immunohistochemically detected HER-2/neu overexpression in 361 patients with ovarian cancer: a multicenter study. Gynecol Oncol 95, 89-94
80Tuefferd M. et al. (2007) HER2 status in ovarian carcinomas: a multicenter GINECO study of 320 patients. PLoS ONE 2, e1138
81Mayr D. et al. (2006) HER-2/neu gene amplification in ovarian tumours: a comprehensive immunohistochemical and FISH analysis on tissue microarrays. Histopathology 48, 149-156
82Lee C.H. et al. (2005) Assessment of Her-1, Her-2, And Her-3 expression and Her-2 amplification in advanced stage ovarian carcinoma. Int J Gynecol Pathol 24, 147-152
83Berek J.S. et al. (2003) Biologic and immunologic therapies for ovarian cancer. J Clin Oncol 21, 168s-174s
84Calzone L. et al. (2008) A comprehensive modular map of molecular interactions in RB/E2F pathway. Mol Syst Biol 4, 173
85Dressman H.K. et al. (2007) An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. J Clin Oncol 25, 517-525
86Agarwal R. and Kaye S.B. (2003) Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer 3, 502-516
87Perou C.M. et al. (2000) Molecular portraits of human breast tumours. Nature 406, 747-752
88Alizadeh A.A. et al. (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503-511
89Chen W. et al. (2008) Mapping translocation breakpoints by next-generation sequencing. Genome Res (May 21, Epub ahead of print)
90Bapat S.A. et al. (2005) Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res 65, 3025-3029
91Bell D.A. (2005) Origins and molecular pathology of ovarian cancer. Mod Pathol 18 (Suppl. 2), S19-S32
92Crum C.P. et al. (2007) The distal fallopian tube: a new model for pelvic serous carcinogenesis. Curr Opin Obstet Gynecol 19, 3-9
Naora H. (2007) The heterogeneity of epithelial ovarian cancers: reconciling old and new paradigms. Expert Rev Mol Med 9, 1-12
Barton C.A. et al. (2008) DNA methylation changes in ovarian cancer: implications for early diagnosis, prognosis and treatment. Gynecol Oncol 109, 129-139
Tan D.S. et al. (2006) Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol 7, 925-934
Hu Y.L. et al. (2003) Dual mechanisms for lysophosphatidic acid stimulation of human ovarian carcinoma cells. J Natl Cancer Inst 95, 733-740
Sherman-Baust C.A. et al. (2003) Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells. Cancer Cell 3, 377-386

For examples of the morphological appearance of different ovarian carcinoma subtypes see:

http://spectrum.med.ubc.ca/pathology/ (username: ovcare; password: diamond. Click on ‘List all Digital Slides’).
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Metrics

Full text views

Total number of HTML views: 4
Total number of PDF views: 37 *
Loading metrics...

Abstract views

Total abstract views: 252 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 22nd October 2017. This data will be updated every 24 hours.