Importance of Chromosomal Changes Correlated to Prognostic Factors in Ovarian and Cervical Malignant Tumors

Česká verzia

Authors: N. Jančárková ¹; M. Krkavcová ²; M. Janashia ²; P. Freitag ¹; J. Dušková ³; D. Cibula ¹
Authors place of work: Gynekologicko–porodnická klinika 1. LF UK a VFN, Praha, Onkogynekologické centrum, přednosta prof. MUDr. A. Martan, DrSc. ¹; Ústav biologie a lékařské genetiky 1. LF UK a VFN, Praha, přednostka doc. MUDr. M. Kohoutová, CSc. ²; Ústav patologie 1. LF UK a VFN, Praha, přednosta prof. MUDr. C. Povýšil, DrSc. ³
Published in the journal: Ceska Gynekol 2008; 73(2): 79-86

Summary

Objective:
The aim of the study was to estimate genetic changes detected in ovarian and cervical cancer cells, in correlation with other available clinical and histopathological parameters, with impact upon cancer prognosis.

Design:
Original article.

Setting:
Department of Gynecology and Obstetrics, First Faculty of Medicine, Charles University in Prague and General Teaching Hospital, Prague.

Methods:
Sixty patients with ovarian cancer and twenty patients with cervical cancer were included in the study. A histopathologist examined the tumor samples in order to define the histological type and grade. MIB-1 and p53 were estimated using an immunohistochemical method. For genetic testing, both conventional and molecular methods were applied (direct culture and a G-banding technique, the FISH method with whole chromosome painting probes, and the CGH method). The results were submitted to statistical evaluation, using analysis of variances and χ² test.

Results.
Numerical and structural chromosomal aberrations were detected in more than 63% of the examined ovarian cancer cases and 29% of examined cervical cancer cases. Ovarian cancer patients with extensive chromosomal rearrangements were significantly younger. The most typical findings in ovarian cancer cells were amplifications 1q, 3q, 20q; and deletions 4p, 4q, 18p, 18q, 19q. The most typical findings in cervical tumor cells were amplifications 3q, 5p; and deletions 13q and isochromosome 5p. Some of the less frequent findings in our study were deletion 22q in 36% of all ovarian cancer samples, as well as amplifications of chromosome 2 and deletions of chromosome 10, 11p, 21q in cervical cancer cells. The activity of proliferative marker MIB-1 was significantly higher in women with a high p53 HSCORE (p < 0.01).

Conclusions.
Chromosomal rearrangements, different for ovarian and cervical cancer, have been found, including several rare findings. The significant importance of genetic alterations and the activity of proliferative markers, including common correlations with an unfavorable outcome in ovarian tumors of younger women were found.

Key words:
ovarian cancer, cervical cancer, chromosomal rearrangements, prognostic factors

Zdroje

1. Allen, DG., White, DJ., Hutchins, AM., et al. Progressive genetic aberrations detected by comparative genomic hybridization in squamous cell cervical cancer. Br J Cancer, 2000, 83, p. 1659-1663.

2. Arnold, N., Hagele, L., Walz, L., et al. Overpresentation of 3q and 8q material and loss of 18q material are recurrent findings in advanced human ovarian cancer. Genes Chromosomes Cancer 1996, 16, p. 46-54.

3. Atkin, NB. Cytogenetics of carcinoma of the cervix uteri: a review. Cancer Genet Cytogenet, 1997, 95, 1, p. 33-39.

4. Bartoňková, H., Foretová, L., Helmichová, E., et al. Doporučené zásady péče o nemocné s nádory prsu a vaječníku a zdravé osoby se zárodečnými mutacemi genů BRCA1 a BRCA2. Klin Onkol, 2003, 16, 1, s. 28-34.

5. Biade, S., Marinucci, M., Schick, J., et al. Gene expression profiling of human ovarian tumors. Br J Cancer, 2006, 95, 8, p. 1092-1100.

6. Bozas, G., Dimopoulos. MA., Kastritis, E., et al. Young age is associated with favorable characteristics but is not an independent prognostic factor in patients with epithelial ovarian cancer : a single institution experience. Oncology, 2006, 70, 4, p. 265-272.

7. Dellas, A., Torhorst, J., Jiang, F., et al. Prognostic value of genomic alterations in invasive cervical squamous cell carcinoma of clinical stage IB detected by comparative genomic hybridization. Cancer Res, 1999, 59, p. 3475-3479.

8. Fishman, A., Shalom-Paz, E., Fejgin, M., et al. Comparing the genetic changes detected in the primary and secondary tumor sites of ovarian cancer using comparative genomic hybridization. Int J Gynecol Cancer, 2005, 15, p. 261-266.

9. Gadducci, A., Di Cristofano, C., Zavaglia, M., et al. P53 gene status in patients with advanced serous epithelial ovarian cancer in relation to response to paclitaxel- plus platinum-based chemotherapy and long-term clinical outcome. Anticancer Res, 2006, 26, 1B, p. 687-693.

10. Gospodarowicz, MK., Henson, DE., Hutter, RVP., eds. Prognostic factors in cancer. 2nd ed. New York: Wiley-Liss, 2001.

11. Guo, Z., Hu, X., Afink, G., et al. Comparison of chromosome 3p deletions between cervical precancers synchronous with and without invasive cancer. Int J Cancer, 2000, 86, p. 518-523.

12. Harris, CP., Lu, XY., Narayan, G., et al. Comprehensive molecular cytogenetic characterization of cervical cancer cell lines. Genes Chromosomes Cancer, 2003, 36, 3, p. 233-241.

13. Hartmann, LC., Lu, KH., Linette, GP., et al. Gene expression profiles predict early relapse in ovarian cancer after platinum-paclitaxel chemotherapy. Clin Cancer Res, 2005, 11, 6, p. 2149-2155.

14. Hauptmann, S., Denkert, C., Koch, I., et al. Genetic alterations in epithelial ovarian tumors analyzed by comparative genomic hybridization. Hum Pathol, 2002, 33, p. 632-641.

15. Helou, K., Padilla-Nash, H., Wangsa, D., et al. Comparative genome hybridization reveals specific genomic imbalances during the genesis from benign through borderline to malignant ovarian tumors. Cancer Genet Cytogenet, 2006, 170, 1, p. 1-8.

16. Heselmeyer-Haddad, K., Janz, V., Castle, PE., et al. Detection and genomic amplification of the human telomerase gene (TERC) in cytologic specimens as a genetic test for the diagnosis of cervical dysplasia. Am J Pathol, 2003, 163, p. 1405-1416.

17. Heselmeyer-Haddad, K., Sommerfield, K., White, NM., et al. Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer. Am J Pathol, 2005, 166, 4, p. 1229-1238.

18. Heselmeyer, K., Macville, M., Schrock, E., et al. Advanced-stage cervical carcinomas are defined by a recurrent pattern of chromosomal aberrations revealing high genetic instability and a consistent gain of chromosome arm 3q. Genes Chromosomes Cancer, 1997, 19, p. 233-240.

19. Hidalgo, A., Schewe, C., Petersen, S., et al. Human papilloma virus status and chromosomal imbalances in primary cervical carcinomas and tumor cell lines. Eur J Cancer, 2000, 36, p. 542-548.

20. Hu, J., Khanna, V., Jones, MM., Surti, U. Comparative study of primary and recurrent serous ovarian carcinomas: comparative genomic hybridization analysis with a potential application for prognosis. Gynecol Oncol, 2003, 89, p. 369-375.

21. Huang, NF., Gupta, M., Varghese, S., et al. Detection of numerical chromosomal abnormalities in epithelial ovarian neoplasmas by fluorescence in situ hybridization (FISH) and a review of the current literature. Appl Immunohistochem Mol Morphol, 2002, 10, 2, p. 187-193.

22. Iwabuchi, H., Sakamoto, M., Sakunaga, H., et al. Genetic analysis of benign, low-grade and high-grade ovarian tumors. Cancer Res, 1995, 55, p. 6172-6180.

23. Kiechle, M., Jacobsen, A., Schwarz-Boeger, U., et al.Comparative genomic hybridization detects genetic imbalances in primary ovarian carcinomas as correlated with grade of differentiation. Cancer, 2001, 91, p. 534-540.

24. Kim, GJ., Kim, JO., Hong, EK., et al. Detection of genetic alterations in Korean ovarian carcinomas by degenerate oligonucleotide primed polymerase-chain reaction – comparative genomic hybridization. Cancer Genet Cytogenet, 2003, 147, p. 23-27.

25. Kim, SW., Kim, JW., Kim, YT., et al. Analysis of chromosomal changes in serous ovarian carcinoma using high-resolution array comparative genomic hybridization: Potential predictive markers of chemoresistant disease. Genes Chromosomes Cancer, 2006, 46, 1, p. 1-9.

26. Kirchhoff, M., Rose, H., Petersen, BL., et al. Comparative genomic hybridization reveals a recurrent pattern of chromosomal aberrations in severe dysplasia/carcinoma in situ of the cervix and in advanced-stage cervical carcinoma. Genes Chromosomes Cancer, 1999, 24, p. 144-150.

27. Mark, HF., Afify, AM., Werness, BA., et al. Trisomy 8 in stage I and stage III ovarian cancer detected by FISH. Exp Mop Pathol, 1999, 66, 1, p. 76-81.

28. Mc Carty, KS. Jr., Miller, LS., Cox, EB., et al. Estrogen receptor analyses: Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med, 1985, 109, p. 716-721.

29. Mian, C., Bancher, D., Kohlberger, P., et al. Fluorescence in situ hybridization in cervical smears: detection of numerical aberrations of chromosomes 7, 3, X and relationship to HPV infection. Gynecol Oncol, 1999, 75, p. 41-46.

30. Mitelman, F. (ed). An International System for Human Cytogenetic Nomenclature. Basel: S. Karger, 1995.

31. Osterberg, L., Akeson, M., Levan, K., et al. Genetic alterations of serous borderline tumors of the ovary compared to stage I serous ovarian carcinomas. Cancer Genet Cytogenet, 2006, 167, 2, p. 103-108.

32. Panani, AD., Roussos, C. Non-random chromosomal changes in ovarian cancer: i(5p) a novel recurrent abnormality. Cancer Letters, 2006, 235, 1, p. 130-135.

33. Santin, AD., Zhan, F., Bellone, S., et al. Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy. Int J Cancer, 2004, 112, 1, p. 14-25.

34. Santos, GdaC., Zielenska, M., Prasad, M., Squire, JA. Chromosome 6p amplification and cancer progression. J Clin Pathol, 2007, 60, p. 1-7.

35. Sham, JS, Tang, TC., Fang, Y., et al. Recurrent chromosome alterations in primary ovarian carcinomas in Chinese women. Cancer Genet Cytogenet, 2002, 133, p. 39-44.

36. Shridhar, V., Lee, J., Pandita, A., et al. Genetic analysis of early- versus late-stage ovarian tumors. Cancer Res, 2001, 61, p. 5895-5904.

37. Sonoda, G., Palazzo, J., du Manoir, S., et al. Comparative genomic hybridization detects frequent overexpression of chromosomal material from 3q26, 8q24 and 20q13 in human ovarian carcinomas. Genes Chromosomes Cancer, 1997, 20, 4, p. 320-328.

38. Spentzos, D., Levine, DA., Kolia, S., et al. Unique gene expression profile based on pathological response in epithelial ovarian cancer. J.Clin Oncol, 2005, 23, 31, p. 7911-7918.

39. Staebler, A., Heselmeyer-Haddad, K., Bell, K., et al. Micropapillary serous carcinoma of the ovary has distinct patterns of chromosomal imbalances by comparative genomic hybridization compared with atypical proliferative serous tumors and serous carcinomas. Hum Pathol, 2002, 33, p. 47-52.

40. Stewart, BW., Kleihues, P. World Cancer Report. Lyon: IARCPress, 2003.

41. Teixeira, NR. Combined classical and molecular cytogenetic analysis of cancer. Eur J Cancer, 2002, 38, 12, p. 1580-1584.

42. Thein, A., Trkova, M., Fox, M., Parrington, J. The application of comparative genomic hybridization to previously karyotyped cervical cancer cell lines. Cancer Genet Cytogenet, 2000, 116, p. 59-65.

43. Tibiletti, MA., Bernasconi, B., Taborelli, M., et al. Genetic and cytogenetic observations among different types of ovarian tumors are compatible with a progression model underlying ovarian tumorigenesis. Cancer Genet Cytogenet, 2003, 146, p. 145-153.

44. Tomsová, M., Melichar, B., Sedláková, I., Nová, M. Prognostické markery u ovariálního karcinomu – retrospektivní studie. Čes Patol, 2005, 41, 2, s. 51-59.

45. Umayahara, K., Numa, F., Inokuma, A., et al. Genetic alterations related to lymph node metastasis and peritoneal dissemination in epithelial ovarian cancer. Oncol Rep, 2002, 9, p. 1115-1119.

46. Umayahara, K., Numa, F., Suehiro, Y., et al. Comparative genomic hybridization detects genetic alterations during early stages of cervical cancer progression. Genes Chromosomes Cancer, 2002, 33, p. 98-102.

47. Wamunyokoli, FW., Bonome, T., Lee, JY., et al. Clin Cancer Res, 2006, 12, 3, p. 690-700.

48. Zimonjic, DB., Simpson, S., Popescu, NC., DiPaolo, JA. Molecular cytogenetic of human papillomavirus-negative cervical carcinoma cell lines. Cancer Genet Cytogenet, 1995, 82, 1, p. 1-8.