Skip to main content

Advertisement

SpringerLink
Log in

Genetic factors in ovarian carcinoma

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Recent evidence indicates that inherited and acquired genetic mutations are the driving force behind carcinogenesis and cellular transformation. This review examines a number of proto-oncogenes and tumor suppressor genes that are associated with ovarian carcinomas, including p53, BRCA1, and BRCA2; mismatch repair genes such as hMSH2 and hMLH1; and PTEN, HER-2/neu, K-ras, fms, and AKT2. Novel genes recently implicated in ovarian tumorigenesis are discussed, including NOEY2, OVCA1, and PIK3CA. Although no singular gene alteration has been shown to initiate transformation in the ovarian epithelium, elucidation of the complex molecular and cellular mechanisms involving these known gene mutations may result in new clinical management strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Risch HA: Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 1998, 90:1774–1784.

    Article  PubMed  CAS  Google Scholar 

  2. Berchuck A, Kohler MF, Hopkins MP, et al.: Overexpression of p53 is not a feature of benign and early stage borderline epithelial ovarian tumors. Gynecol Oncol 1994, 52:232–234.

    Article  PubMed  CAS  Google Scholar 

  3. DiCioccio RA, Werness BA, Peng R, et al.: Correlation of TP53 mutations and p53 expression in ovarian tumors. Cancer Genet Cytogenet 1998, 105:93–102.

    Article  PubMed  CAS  Google Scholar 

  4. Casey G, Lopez ME, Ramos JC, et al.: 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.

    PubMed  CAS  Google Scholar 

  5. Chan WY, Cheung KK, Schorge JO, et al.: Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers. Am J Pathol 2000, 156:409–417. This report examines the relationship between bcl-2 and p53 protein expression and correlates apoptosis with p53 mutation but not bcl-2 expression.

    PubMed  CAS  Google Scholar 

  6. Nielson LL, Pegram M, Karlan B, et al.: Opportunities for p53 tumor suppressor gene therapy in ovarian and other peritoneal cancers. In Adenoviruses: Basic Biology to Gene Therapy. Edited by Seth P. Georgetown, TX: RG Landes; 1999:293–301.

    Google Scholar 

  7. Mujoo K, Catino JJ, Maneval DC, Gutterman JU: Studies on the molecular mechanism of growth inhibition with p53 adenoviral construct in human ovarian cancer. Int J Gynecol Cancer 1998, 8:233–241.

    Article  Google Scholar 

  8. Mujoo K, Maneval DC, Anderson SC, Gutterman JU: Adenoviralmediated p53 tumor suppressor gene therapy of human ovarian carcinoma. Oncogene 1996, 12:1617–1623.

    PubMed  CAS  Google Scholar 

  9. Narod SA, Ford D, Divilee P, et al.: An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Am J Hum Genet 1995, 56:254–264.

    PubMed  CAS  Google Scholar 

  10. Miki Y, Swensen J, Shattuck-Eidens D, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994, 266:66–71.

    Article  PubMed  CAS  Google Scholar 

  11. Jensen RA, Thompson ME, Jetton TL, et al.: BRCA1 is secreted and exhibits properties of a granin. Nat Genet 1996, 12:303–308.

    Article  PubMed  CAS  Google Scholar 

  12. Gayther SA, Mangion J, Russell P, et al.: Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 1997, 15:103–105.

    Article  PubMed  CAS  Google Scholar 

  13. Gayther SA, Warren W, Mazoyer S, et al.: Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet 1995, 11:428–233.

    Article  PubMed  CAS  Google Scholar 

  14. Shattuck-Eidens D, McClure M, Simard J, et al.: A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene: implications for presymptomatic testing and screening. JAMA 1995, 273:535–541.

    Article  PubMed  CAS  Google Scholar 

  15. Rhei E, Bogomolniy F, Federici MG, et al.: Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers. Cancer Res 1998, 58:3198–3196.

    Google Scholar 

  16. Ramus SJ, Bobrow LG, Pharoah PD, et al.: Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours. Genes Chromosomes Cancer 1999, 25:91–96.

    Article  PubMed  CAS  Google Scholar 

  17. Zweemer RP, Shaw PA, Verheijen MH, et al.: Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations. J Clin Pathol 1999, 52:372–375.

    Article  PubMed  CAS  Google Scholar 

  18. Holt JT, Thompson ME, Szabo C, et al.: Growth retardation and tumour inhibition by BRCA1. Nat Genet 1996, 12:298–302.

    Article  PubMed  CAS  Google Scholar 

  19. Zhong Q, Chen CF, Li S, et al.: Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science 1999, 285:747–750.

    Article  PubMed  CAS  Google Scholar 

  20. Fan S, Wang JA, Yuan R, et al.: BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science 1999, 284:1354–1356. This study links BRCA1 mutations to transcriptional regulation of estrogen receptor-a signaling in cell proliferation.

    Article  PubMed  CAS  Google Scholar 

  21. Aprelikova ON, Fang BS, Meissner EG, et al.: BRCA1-associated growth arrest is RB-dependent. Proc Natl Acad Sci U S A 1999, 96:11866–11871. These authors evaluated a panel of cell lines for the ability to reduce colony outgrowth associated with BRCA1 overexpression and determined that inactivation of pRb by HPV E7 abrogates the growth arrest by BRCA1.

    Article  PubMed  CAS  Google Scholar 

  22. Lynch HT, Casey MJ, Lynch J, et al.: Genetics and ovarian carcinoma. Semin Oncol 1998, 25:265–280.

    PubMed  CAS  Google Scholar 

  23. Zhang H, Richards B, Wilson T, et al.: Apoptosis induced by overexpression of hMSH2 or hMLH1. Cancer Res 1999, 59:3021–3027.

    PubMed  CAS  Google Scholar 

  24. Li J, Yen C, Liaw D, et al.: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275:1943–1947.

    Article  PubMed  CAS  Google Scholar 

  25. Maxwell GL, Risinger JI, Tong B, et al.: Mutation of the PTEN tumor suppressor gene is not a feature of ovarian cancers. Gynecol Oncol 1998, 70:13–16.

    Article  PubMed  CAS  Google Scholar 

  26. Saito M, Okamoto A, Kohno T, et al.: Allelic imbalance and mutations of the PTEN gene in ovarian cancer. Int J Cancer 2000, 85:160–165.

    PubMed  CAS  Google Scholar 

  27. Minaguchi T, Mori T, Kanamori Y, et al.: Growth suppression of human ovarian cancer cells by adenovirus-mediated transfer of the PTEN gene. Cancer Res 1999, 59:6063–6067. This study investigated transduction of PTEN as a candidate for adenovirus vector-based gene therapy.

    PubMed  CAS  Google Scholar 

  28. Yu Y, Xu F, Peng H, et al.: NOEY2: an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proc Natl Acad Sci U S A 1999, 96:214–219. Using differential display PCR, these authors report a novel gene whose function is abrogated in ovarian and breast cancers.

    Article  PubMed  CAS  Google Scholar 

  29. Schultz DC, Vanderveer L, Berman DB, et al.: Identification of two candidate tumor suppressor genes on chromosome 17p13.3. Cancer Res 1996, 56:1997–2002.

    PubMed  CAS  Google Scholar 

  30. Bruening W, Prowse AH, Schultz DC, et al.: Expression of OVCA1, a candidate tumor suppressor, is reduced in tumors and inhibits growth of ovarian cancer cells. Cancer Res 1999, 59:4973–4983.

    PubMed  CAS  Google Scholar 

  31. Yu DH, Hung MC: Expression of activated rat neu oncogene is sufficient to induce experimental metastasis in 3T3 cells. Oncogene 1991, 6:1991–1996.

    PubMed  CAS  Google Scholar 

  32. Hengstler JG, Lange J, Kett A, et al.: Contribution of c-erbB-2 and topoisomerase IIa to chemoresistance in ovarian cancer. Cancer Res 1999, 59:3206–3214.

    PubMed  CAS  Google Scholar 

  33. Goldenberg MM: Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin Ther 1999, 21:309–318.

    Article  PubMed  CAS  Google Scholar 

  34. Le XF, McWatters A, Wiener J, et al.: Anti-HER2 antibody and heregulin suppress growth of HER2-overexpressing human breast cancer cells through different mechanisms. Clin Cancer Res 2000, 6:260–270.

    PubMed  CAS  Google Scholar 

  35. Caduff RF, Svoboda-Newman SM, Ferguson AW, et al.:Comparison of mutations of Ki-ras and p53 immunoreactivity in borderline and malignant epithelial ovarian tumors. Am J Surg Pathol 1999, 23:323–328.

    Article  PubMed  CAS  Google Scholar 

  36. Baiocchi G, Kavanaugh JJ, Talpaz M, et al.: Expression of macrophage colony stimulating factor and its receptor in gynecologic malignancies. Cancer 1991, 67:990–906.

    Article  PubMed  CAS  Google Scholar 

  37. Chambers SK, Kacinski BM, Ivins CM, Carcangiu M: Overexpression of epithelial macrophage colony-stimulating factor (CSF-1) and CSF-1 receptor: a poor prognostic factor in epithelial ovarian cancer, contrasted with a protective effect of stromal CSF-1. Clin Cancer Res 1997, 3:999–1007.

    PubMed  CAS  Google Scholar 

  38. Yokoyama Y, Morishita S, Takahasi Y, et al.: Modulation of c-fms proto-oncogene in an ovarian carcinoma cell line by a hammerhead ribozyme. Brit J Cancer 1997, 76(8):977–82.

    PubMed  CAS  Google Scholar 

  39. Bellacosa A, de Feo D, Godwin AK, et al.: Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 1995, 65:220–285.

    Google Scholar 

  40. Liu AX, Testa JR, Hamilton TC: AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidyllinositol 3-kinase in human ovarian epithelial cancer cells. Cancer Res 1998, 58:2973–2977.

    PubMed  CAS  Google Scholar 

  41. Knuutila S, Bjorkqvist AM, Autio K, et al.: DNA copy number amplifications in human neoplasms. Am J Pathol 1998, 152:1107–1123. An excellent review of comparative genomic hybridization techniques and DNA sequence copy number amiplifications in human neoplasms.

    PubMed  CAS  Google Scholar 

  42. Shayesteh L, Lu Y, Kuo WL, et al.: PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 1999, 21:99–102. This study suggests PIK3CA as an oncogene with specific activity in ovarian carcinomas.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Obstetrics and Gynecology, UCLA/Cedars Sinai Health System, 8635 West 3rd Street #160-W, 90048, Los Angeles, CA, USA

    Andrew J. Li MD & Beth Y. Karlan MD

Authors
  1. Andrew J. Li MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Beth Y. Karlan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, A.J., Karlan, B.Y. Genetic factors in ovarian carcinoma. Curr Oncol Rep 3, 27–32 (2001). https://doi.org/10.1007/s11912-001-0039-y

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-001-0039-y

Keywords

Search

Navigation