17Ovarian Cancer

In women, the ovaries produce eggs for reproduction. There are three main types ofovarian tumors (American Cancer Association):

1. Germ cell tumors start from the cells that produce the ova (eggs) (Figure 17.1).

2. Stromal tumors start from connective tissue cells that hold the ovary togetherand produce the female hormones estrogen and progesterone.

3. Epithelial tumors start from the cells that cover the outer surface of the ovary.

Epithelial ovarian carcinomas constitute 85–90% of all ovarian cancers and aredivided into serous, mucinous, endometrioid, and clear cell types.

More than 50% of women survive more than five years after diagnosis of ovariancancer.

Diagnosis is by biopsy and various imaging techniques: X-ray, ultrasound, andmagnetic resonance. Ovarian cancer, like many other cancers, is staged according tothe AJCC/TNM System.

Treatment consists of surgery, radiation therapy, and chemotherapy.

17.1 MICROARRAY STUDIES OF OVARIAN CANCER

17.1.1 Duke University Medical Center

Lancaster et al. (2004) published a study of 42 advanced stage ovarian cancers frompatients who survived either less than two years or more than seven years. Geneexpression patterns associated with survival were identified.

Cancer Diagnostics with DNA Microarrays, By Steen KnudsenCopyright c© 2006 John Wiley & Sons, Inc.

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MICROARRAY STUDIES OF OVARIAN CANCER 131

Epithelium

Connective tissueFollicle

Oocyte

Figure 17.1 Histology of the ovary. (From Tortora, Principles of Human Anatomy, 10th ed., 2005,p. 853. Used with permission of John Wiley & Sons, Inc.)

17.1.2 The Stanford Group

Schaner et al. (2003) published a study of 59 archived ovarian cancer samples usingthree different cDNA microarrays based on IMAGE clones. Thirty-nine samples repre-sented serous papillary carcinomas, 7 clear cell, 2 endometrial, 4 undifferentiated, and3 adenocarcinomas. A group of genes that distinguished clear cell from other ovariancarcinomas was identified. Clear cell subtype is associated with a worse prognosis andtherapeutic resistance. In addition, it was possible to distinguish between breast andovarian cancer and between different grades of ovarian cancer.

17.1.3 The London Group

Adib et al. (2004) published a study of ovarian cancers using Affymetrix U95A arrays.They found that the expression profile of primary and secondary tumors from thesame individual were essentially alike. They also found a biomarker, mammaglobin-2(MGB2), which is specific to ovarian cancer.

17.1.4 The UCLA Group

Matei et al. (2002) published a study of 9 normal ovaries and 21 epithelial ovariancarcinomas. Hierarchical clustering revealed a clear distinction between normal tissueand carcinoma.

17.1.5 The NIH Group

Sawiris et al. (2002) published a description of their Ovachip, containing 516 cDNAschosen from serial analysis of gene expression in ovarian cancer. The Ovachip wasshown to be highly accurate in distinguishing between ovarian cancer and colon cancer.

132 OVARIAN CANCER

17.1.6 The Novartis Group

Welsh et al. (2001b) published a study of 27 serous papillary adenocarcinomas of theovary and three normal ovarian samples using an Affymetrix HuGeneFL array wafer.Hierarchical clustering revealed subgroups consistent with known clinical features.

17.2 SUMMARY

The study of ovarian cancer with microarrays is dominated by small studies with fewsamples and few genes. They do agree, however, that it is possible to differentiatebetween metatstatic and nonmetastatic or between survival and nonsurvival. Morestudies with larger populations are needed. Several studies have also shown the abilityof DNA microarrays to differentiate between ovarian cancer and colon, breast, anduterine cancer.

FURTHER READING

Haviv, I., and Campbell, I. G. (2002). DNA microarrays for assessing ovarian cancer geneexpression. Mol. Cell. Endocrinol. 191(1):121–126 (review).

Hibbs, K., Skubitz, K. M., Pambuccian, S. E., Casey, R. C., Burleson, K. M., Oegema, T. R.,Thiele, J. J., Grindle, S. M., Bliss, R. L., and Skubitz, A. P. (2004). Differential geneexpression in ovarian carcinoma: identification of potential biomarkers. Am. J. Pathol.165(2):397–414.

Hough, C. D., Cho, K. R., Zonderman, A. B., Schwartz, D. R., and Morin, P. J. (2001). Coor-dinately up-regulated genes in ovarian cancer. Cancer Res. 61(10):3869–3876.

Ismail, R. S., Baldwin, R. L., Fang, J., Browning, D., Karlan, B. Y., Gasson, J. C., andChang, D. D. (2000). Differential gene expression between normal and tumor-derived ovarianepithelial cells. Cancer Res. 60(23):6744–6749.

Lee, B. C., Cha, K., Avraham, S., and Avraham, H. K. (2004). Microarray analysis of differen-tially expressed genes associated with human ovarian cancer. Int. J. Oncol. 24(4):847–851.

Martoglio, A. M., Tom, B. D., Starkey, M., Corps, A. N., Charnock-Jones, D. S., andSmith, S. K. (2000). Changes in tumorigenesis- and angiogenesis-related gene transcriptabundance profiles in ovarian cancer detected by tailored high density cDNA arrays. Mol.Med. 6(9):750–765.

Nishizuka, S., Chen, S. T., Gwadry, F. G., Alexander, J., Major, S. M., Scherf, U., Rein-hold, W. C., Waltham, M., Charboneau, L., Young, L., Bussey, K. J., Kim, S., Lababidi, S.,Lee, J. K., Pittaluga, S., Scudiero, D. A., Sausville, E. A., Munson, P. J., Petricoin, E. F.,Liotta, L. A., Hewitt, S. M., Raffeld, M., and Weinstein, J. N. (2003). Diagnostic markersthat distinguish colon and ovarian adenocarcinomas: identification by genomic, proteomic,and tissue array profiling. Cancer Res. 63(17):5243–5250.

Presneau, N., Mes-Masson, A. M., Ge, B., Provencher, D., Hudson, T. J., and Tonin, P. N.(2003). Patterns of expression of chromosome 17 genes in primary cultures of normal ovariansurface epithelia and epithelial ovarian cancer cell lines. Oncogene 22(10):1568–1579.

FURTHER READING 133

Sakamoto, M., Kondo, A., Kawasaki, K., Goto, T., Sakamoto, H., Miyake, K., Koyamatsu, Y.,Akiya, T., Iwabuchi, H., Muroya, T., Ochiai, K., Tanaka, T., Kikuchi, Y., and Tenjin, Y.(2001). Analysis of gene expression profiles associated with cisplatin resistance in humanovarian cancer cell lines and tissues using cDNA microarray. Hum. Cell 14(4):305–315.

Santin, A. D., Zhan, F., Bellone, S., Palmieri, M., Cane, S., Gokden, M., Roman, J. J.,O’Brien, T. J., Tian, E., Cannon, M. J., Shaughnessy, J., and Pecorelli, S. (2004). Discrimi-nation between uterine serous papillary carcinomas and ovarian serous papillary tumours bygene expression profiling. Br. J. Cancer 90(9):1814–1824.

Santin, A. D., Zhan, F., Bellone, S., Palmieri, M., Cane, S., Bignotti, E., Anfossi, S., Gok-den, M., Dunn, D., Roman, J. J., O’Brien, T. J., Tian, E., Cannon, M. J., Shaughnessy, J.,and Pecorelli, S. (2004). Gene expression profiles in primary ovarian serous papillary tumorsand normal ovarian epithelium: identification of candidate molecular markers for ovariancancer diagnosis and therapy. Int. J. Cancer 112(1):14–25.

Schwartz, D. R., Kardia, S. L., Shedden, K. A., Kuick, R., Michailidis, G., Taylor, J. M.,Misek, D. E., Wu, R., Zhai, Y., Darrah, D. M., Reed, H., Ellenson, L. H., Giordano, T. J.,Fearon, E. R., Hanash, S. M., and Cho, K. R. (2002). Gene expression in ovarian cancerreflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res. 62(16):4722–4729.

Spentzos, D., Levine, D. A., Kolia, S., Otu, H., Boyd, J., Libermann, T. A., and Cannis-tra, S. A. (2005). Unique gene expression profile based on pathologic response in epithelialovarian cancer. J. Clin. Oncol. 23(31):7911–7918.

Tapper, J., Kettunen, E., El-Rifai, W., Seppala, M., Andersson, L. C., and Knuutila, S. (2001).Changes in gene expression during progression of ovarian carcinoma. Cancer Genet. Cyto-genet. 128(1):1–6.

Tonin, P. N., Hudson, T. J., Rodier, F., Bossolasco, M., Lee, P. D., Novak, J., Mander-son, E. N., Provencher, D., and Mes-Masson, A. M. (2001). Microarray analysis of geneexpression mirrors the biology of an ovarian cancer model. Oncogene 20(45):6617–6626.

Wang, K., Gan, L., Jeffery, E., Gayle, M., Gown, A. M., Skelly, M., Nelson, P. S., Ng, W. V.,Schummer, M., Hood, L., and Mulligan, J. (1999). Monitoring gene expression profilechanges in ovarian carcinomas using cDNA microarray. Gene 229(1-2):101–108.

Wong, K. K., Cheng, R. S., and Mok, S. C. (2001). Identification of differentially expressedgenes from ovarian cancer cells by MICROMAX cDNA microarray system. Biotechniques30(3):670–675.

Xu, S., Mou, H., Lu, G., Zhu, C., Yang, Z., Gao, Y., Lou, H., Liu, X., Cheng, Y., and Yang, W.(2002). Gene expression profile differences in high and low metastatic human ovarian cancercell lines by gene chip. Chin. Med. J. (Engl.) 115(1):36–41.