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Laboratory of Molecular Genetics of Female Reproductive Cancer

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OVARIAN CANCER RESEARCH PROGRAM

Objectives
The long-term objectives of our research team are:
- Molecular pathogenesis of ovarian serous carcinoma
- Biomarker discovery, validation and characterization, and development of new micro-fluid based devices for early diagnosis of ovarian cancer in high-risk patients
- Application of target-based therapeutics from pre-clinical models to clinical trials
Research Program
The Ovarian Cancer Research Program includes 9 research groups and an Ovarian Cancer Pathology core.

B. Ovarian cancer genomics (Tian-Li Wang, Victor Velculescu, Ie-Ming Shih, Robert J. Kurman)

Drs. Wang and Shih have assessed DNA copy number changes among affinity-purified tumor cells from ovarian serous neoplasms including serous borderline tumors, low-grade (LG) and high-grade (HG) serous carcinomas [3, 9]. Their findings indicate chromosomal instability is a cardinal feature of HG carcinoma and suggest that ch1p36 deletion (the locus harbors CHD5 and miR-34a) is associated with the progression from serous borderline tumor to LG carcinoma. The investigators in this group has also identified several new amplified candidate oncogenes and deleted tumor suppressors in ovarian cancer. Their study based on purified tumor samples complements the Cancer Genome Atlas (TCGA) and provides a genome-wide homozygous deletion and amplification profile in HG serous carcinomas which can serve as a molecular foundation to study new oncogenes and tumor suppressors in ovarian cancer [10, 11].

References

1. Cho, K.R., and Shih, I.M. (2009). Ovarian cancer. Annu Rev Pathol Mech Dis 4, 287-313.

2. Kuo, K.T., Mao, T.L., Jones, S., Veras, E., Ayhan, A., Wang, T.L., Glas, R., Slamon, D., Velculescu, V.E., Kuman, R.J., and Shih Ie, M. (2009). Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol 174, 1597-1601.

3. Kuo, K.T., Guan, B., Feng, Y., Mao, T.L., Chen, X., Jinawath, N., Wang, Y., Kurman, R.J., Shih, I.M., and Wang, T.L. (2009). Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-Grade and High-Grade Carcinomas. Cancer Res 69, 4036-4042.

4. Salani, R., Kurman, R.J., Giuntoli, R., 2nd, Gardner, G., Bristow, R., Wang, T.L., and Shih, I.M. (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.

5. Singer, G., Kurman, R.J., Chang, H.-W., Cho, S.K.R., and Shih, I.-M. (2002). Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol 160, 1223-1228.

6. Singer, G., Oldt, R., 3rd, Cohen, Y., Wang, B.G., Sidransky, D., Kurman, R.J., and Shih Ie, M. (2003). Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95, 484-486.

7. Singer, G., Shih Ie, M., Truskinovsky, A., Umudum, H., and Kurman, R.J. (2003). Mutational Analysis of K-ras Segregates Ovarian Serous Carcinomas into Two Types: Invasive MPSC (Low-grade Tumor) and Conventional Serous Carcinoma (High-grade Tumor). Int J Gynecol Pathol 22, 37-41.

8. Singer, G., Stohr, R., Cope, L., Dehari, R., Hartmann, A., Cao, D.F., Wang, T.L., Kurman, R.J., and Shih, I.M. (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.

9. Nakayama, K., Nakayama, N., Jinawath, N., Salani, R., Kurman, R.J., Shih Ie, M., and Wang, T.L. (2007). Amplicon profiles in ovarian serous carcinomas. Int J Cancer 120, 2613-2617.

10. Nakayama, K., Nakayama, N., Davidson, B., Katabuchi, H., Kurman, R.J., Velculescu, V.E., Shih Ie, M., and Wang, T.L. (2006). Homozygous Deletion of MKK4 in Ovarian Serous Carcinoma. Cancer Biol Ther 5, 630-634.

11. Nakayama, K., Nakayama, N., Kurman, R.J., Cope, L., Pohl, G., Samuels, Y., Velculescu, V.E., Wang, T.L., and Shih Ie, M. (2006). Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol Ther 5, 779-785.

12. Shih Ie, M., Sheu, J.J., Santillan, A., Nakayama, K., Yen, M.J., Bristow, R.E., Vang, R., Parmigiani, G., Kurman, R.J., Trope, C.G., Davidson, B., and Wang, T.L. (2005). Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma. Proc Natl Acad Sci U S A 102, 14004-14009.

13. Nakayama, K., Nakayama, N., Davidson, B., Sheu, J.J., Jinawath, N., Santillan, A., Salani, R., Bristow, R.E., Morin, P.J., Kurman, R.J., Wang, T.L., and Shih, I.M. (2006). A BTB/POZ protein, NAC-1, is related to tumor recurrence and is essential for tumor growth and survival. Proc Natl Acad Sci U S A.

14. Choi, J.H., Sheu, J.J., Guan, B., Jinawath, N., Markowski, P., Wang, T.L., and Shih Ie, M. (2009). Functional analysis of 11q13.5 amplicon identifies Rsf-1 (HBXAP) as a gene involved in paclitaxel resistance in ovarian cancer. Cancer Res 69, 1407-1415.

15. Sheu, J.J., Choi, J.H., Yildiz, I., Tsai, F.J., Shaul, Y., Wang, T.L., and Shih, I.M. (2008). The Roles of Human Sucrose Nonfermenting Protein 2 Homologue in the Tumor-Promoting Functions of Rsf-1. Cancer Res 68, 4050-4057.

16. Mao, T.L., Hsu, C.Y., Yen, M.J., Gilks, B., Sheu, J.J., Gabrielson, E., Vang, R., Cope, L., Kurman, R.J., Wang, T.L., and Shih Ie, M. (2006). Expression of Rsf-1, a chromatin-remodeling gene, in ovarian and breast carcinoma. Hum Pathol 37, 1169-1175.

17. Davidson, B., Berner, A., Trope, C.G., Wang, T.L., and Shih Ie, M. (2007). Expression and clinical role of the bric-a-brac tramtrack broad complex/poxvirus and zinc protein NAC-1 in ovarian carcinoma effusions. Hum Pathol 38, 1030-1036.

18. Davidson, B., Elstrand, M.B., McMaster, M.T., Berner, A., Kurman, R.J., Risberg, B., Trope, C.G., and Shih Ie, M. (2005). HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma. Gynecol Oncol 96, 42-47.

19. Jinawath, N., Vasoontara, C., Yap, K.L., Thiaville, M.M., Nakayama, K., Wang, T.L., and Shih, I.M. (2009). NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway. Oncogene 28, 1941-1948.

20. Chen, Y.C., Davidson, B., Cheng, C.C., Maitra, A., Giuntoli, R.L., 2nd, Hruban, R.H., Wang, T.L., and Shih Ie, M. (2005). Identification and characterization of membralin, a novel tumor-associated gene, in ovarian carcinoma. Biochim Biophys Acta 1730, 96-102.

21. Chen, Y.-C., Pohl, G., Wang, T.-L., Morin, P.J., Risberg, B., Kristensen, G., Yu, A., Davidson, B., and Shih, I.-M. (2005). Apolipoprotein E is required for cell proliferation and survival in ovarian cancer. Cancer Res 65, 331-337.

22. Sherman-Baust, C.A., Weeraratna, A.T., Rangel, L.B., Pizer, E.S., Cho, K.R., Schwartz, D.R., Shock, T., and Morin, P.J. (2003). Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells. Cancer Cell 3, 377-386.

23. Li, C., and Wong, W.H. (2001). Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci U S A 98, 31-36.

24. Yeh, H.C., Ho, Y.P., Shih Ie, M., and Wang, T.H. (2006). Homogeneous point mutation detection by quantum dot-mediated two-color fluorescence coincidence analysis. Nucleic Acids Res 34, e35.

25. Zhang, Z., Bast, R.C., Jr., Yu, Y., Li, J., Sokoll, L.J., Rai, A.J., Rosenzweig, J.M., Cameron, B., Wang, Y.Y., Meng, X.Y., Berchuck, A., Van Haaften-Day, C., Hacker, N.F., de Bruijn, H.W., van der Zee, A.G., Jacobs, I.J., Fung, E.T., and Chan, D.W. (2004). Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 64, 5882-5890.

26. Rai, A.J., Zhang, Z., Rosenzweig, J., Shih Ie, M., Pham, T., Fung, E.T., Sokoll, L.J., and Chan, D.W. (2002). Proteomic approaches to tumor marker discovery. Arch Pathol Lab Med 126, 1518-1526.

27. Wang, Y., Kuhajda, F.P., Sokoll, L.J., and Chan, D.W. (2001). Two-site ELISA for the quantitative determination of fatty acid synthase. Clin Chim Acta 304, 107-115.

28. Singer, G., Rebmann, V., Chen, Y.C., Liu, H.T., Ali, S.Z., Reinsberg, J., McMaster, M.T., Pfeiffer, K., Chan, D.W., Wardelmann, E., Grosse-Wilde, H., Cheng, C.C., Kurman, R.J., and Shih Ie, M. (2003). HLA-G is a potential tumor marker in malignant ascites. Clin Cancer Res 9, 4460-4464.

29. Naora, H., Montz, F.J., Chai, C.Y., and Roden, R.B. (2001). Aberrant expression of homeobox gene HOXA7 is associated with mullerian-like differentiation of epithelial ovarian tumors and the generation of a specific autologous antibody response. Proc Natl Acad Sci U S A 98, 15209-15214.

30. Naora, H., Yang, Y.Q., Montz, F.J., Seidman, J.D., Kurman, R.J., and Roden, R.B. (2001). A serologically identified tumor antigen encoded by a homeobox gene promotes growth of ovarian epithelial cells. Proc Natl Acad Sci U S A 98, 4060-4065.

31. Tsai-Turton, M., Santillan, A., Lu, D., Bristow, R.E., Chan, K.C., Shih, I.M., and Roden, R.B. (2009). p53 autoantibodies, cytokine levels and ovarian carcinogenesis. Gynecol Oncol.

32. Wang, B.G., Huang, H.Y., Chen, Y.C., Bristow, R.E., Kassauei, K., Cheng, C.C., Roden, R., Sokoll, L.J., Chan, D.W., and Shih Ie, M. (2003). Increased plasma DNA integrity in cancer patients. Cancer Res 63, 3966-3968.

33. Chang, H.W., Ali, S.Z., Cho, S.K., Kurman, R.J., and Shih Ie, M. (2002). Detection of allelic imbalance in ascitic supernatant by digital single nucleotide polymorphism analysis. Clin Cancer Res 8, 2580-2585.

34. Chang, H.W., Lee, S.M., Goodman, S.N., Singer, G., Cho, S.K., Sokoll, L.J., Montz, F.J., Roden, R., Zhang, Z., Chan, D.W., Kurman, R.J., and Shih Ie, M. (2002). Assessment of plasma DNA levels, allelic imbalance, and CA 125 as diagnostic tests for cancer. J Natl Cancer Inst 94, 1697-1703.

35. Salani, R., Davidson, B., Fiegl, M., Marth, C., Muller-Holzner, E., Gastl, G., Huang, H.Y., Hsiao, J.C., Lin, H.S., Wang, T.L., Lin, B.L., and Shih Ie, M. (2007). Measurement of cyclin E genomic copy number and strand length in cell-free DNA distinguish malignant versus benign effusions. Clin Cancer Res 13, 5805-5809.

36. Buckhaults, P., Zhang, Z., Chen, Y.C., Wang, T.L., St Croix, B., Saha, S., Bardelli, A., Morin, P.J., Polyak, K., Hruban, R.H., Velculescu, V.E., and Shih Ie, M. (2003). Identifying tumor origin using a gene expression-based classification map. Cancer Res 63, 4144-4149.

37. Shih Ie, M., Salani, R., Fiegl, M., Wang, T.L., Soosaipillai, A., Marth, C., Muller-Holzner, E., Gastl, G., Zhang, Z., and Diamandis, E.P. (2007). Ovarian cancer specific kallikrein profile in effusions. Gynecol Oncol 105, 501-507.

38. Rangel, L.B., Agarwal, R., D'Souza, T., Pizer, E.S., Alo, P.L., Lancaster, W.D., Gregoire, L., Schwartz, D.R., Cho, K.R., and Morin, P.J. (2003). Tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer but not in ovarian cystadenomas. Clin Cancer Res 9, 2567-2575.

39. D'Souza, T., Agarwal, R., and Morin, P.J. (2005). Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent protein kinase regulates tight junction barrier function in ovarian cancer cells. J Biol Chem 280, 26233-26240.

40. Hung, C.F., Tsai, Y.C., He, L., Coukos, G., Fodor, I., Qin, L., Levitsky, H., and Wu, T.C. (2007). Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice. Gene Ther 14, 20-29.

41. Chang, C.L., Ma, B., Pang, X., Wu, T.C., and Hung, C.F. (2009). Treatment With Cyclooxygenase-2 Inhibitors Enables Repeated Administration of Vaccinia Virus for Control of Ovarian Cancer. Mol Ther.

42. Chang, C.L., Tsai, Y.C., He, L., Wu, T.C., and Hung, C.F. (2007). Cancer immunotherapy using irradiated tumor cells secreting heat shock protein 70. Cancer Res 67, 10047-10057.

43. Choi, Y.S., Hoory, T., Monie, A., Wu, A., Connolly, D., and Hung, C.F. (2008). alpha-Galactosylceramide enhances the protective and therapeutic effects of tumor cell based vaccines for ovarian tumors. Vaccine 26, 5855-5863.

44. Park, J.T., Li, M., Nakayama, N., Davidson, B., Eberhart, C.G., Kurman, R.J., Shih, I.-M., and Wang, T.-L. (2006). Notch-3 gene amplification in ovarian cancer. Cancer Res 66, 6312-6318.

45. Shih, I.M., and Wang, T.L. (2007). Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res 67, 1879-1882. 46. Park, J.T., Shih Ie, M., and Wang, T.L. (2008). Identification of pbx1, a potential oncogene, as a notch3 target gene in ovarian cancer. Cancer Res 68, 8852-8860.

47. Armstrong, D.K., Bundy, B., Wenzel, L., Huang, H.Q., Baergen, R., Lele, S., Copeland, L.J., Walker, J.L., and Burger, R.A. (2006). Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354, 34-43.

48. Armstrong, D.K., Fleming, G.F., Markman, M., and Bailey, H.H. (2006). A phase I trial of intraperitoneal sustained-release paclitaxel microspheres (Paclimer(R)) in recurrent ovarian cancer: A Gynecologic Oncology Group study. Gynecol Oncol.

49. Jorgensen, T.J., Helzlsouer, K.J., Clipp, S.C., Bolton, J.H., Crum, R.M., and Visvanathan, K. (2009). DNA repair gene variants associated with benign breast disease in high cancer risk women. Cancer Epidemiol Biomarkers Prev 18, 346-350.

50. Visvanathan, K., Chlebowski, R.T., Hurley, P., Col, N.F., Ropka, M., Collyar, D., Morrow, M., Runowicz, C., Pritchard, K.I., Hagerty, K., Arun, B., Garber, J., Vogel, V.G., Wade, J.L., Brown, P., Cuzick, J., Kramer, B.S., and Lippman, S.M. (2009). American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction. J Clin Oncol.

51. Kurman, R.J., and Shih Ie, M. (2008). Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol 27, 151-160.

52. Burks, R.T., Sherman, M.E., and Kurman, R.J. (1996). Micropapillary serous carcinoma of the ovary. A distinctive low-grade carcinoma related to serous borderline tumors. Am J Surg Pathol 20, 1319-1330.

53. Seidman, J.D., Horkayne-Szakaly, I., Haiba, M., Boice, C.R., Kurman, R.J., and Ronnett, B.M. (2003). The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol 23, 41-44.

54. Seidman, J.D., Horkayne-Szakaly, I., Haiba, M., Boice, C.R., Kurman, R.J., and Ronnett, B.M. (2004). The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol 23, 41-44.

55. Seidman, J.D., and Kurman, R.J. (2000). Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators. Hum Pathol 31, 539-557.

56. Seidman, J.D., and Kurman, R.J. (1996). Subclassification of serous borderline tumors of the ovary into benign and malignant types. A clinicopathologic study of 65 advanced stage cases. Am J Surg Pathol 20, 1331-1345.

57. Shih, I.-M., and Kurman, R.J. (2004). Ovarian tumorigenesis- a proposed model based on morphological and molecular genetic analysis. Am J Pathol 164, 1511-1518.

58. Kurman, R.J., Visvanathan, K., Roden, R., Wu, T.C., and Shih Ie, M. (2008). Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. Am J Obstet Gynecol 198, 351-356.