Future Perspectives In Studying Ovarian Tumors

The tumorigenesis model described here provides a framework for future molecular and clinical studies of ovarian cancer (64). There are several research directions that need to be addressed in order to better understand the pathogenesis of ovarian carcinoma. The most critical include the introduction of new molecular genetic tools and population-based studies of ovarian serous borderline tumors. First, the key molecular events that are involved in the development of different subtypes of ovarian carcinoma are largely unknown. Several elegant studies have used gene expression profiling as the discovery tool and have identified a myriad of candidate markers associated in ovarian cancer. Although, this expression-based approach is intriguing, these studies alone can not distinguish the cancer "driving" genes that directly propel tumor progression from a larger number of "passenger" genes that are concurrently overexpressed, but lack biological relevance in tumor development. This is because gene expression is dynamic and depends on both genetic and epigenetic programs in tumor cells. In contrast, molecular genetic changes, such as alterations in DNA copy number (e.g., amplifications and deletions), and point mutations are inheritable in nature and are the result of Darwinian selection because of the growth advantage conferred by these alterations in tumors (65). The success of the human genome database and sequence assembly has accelerated cancer genome studies, and it is providing precise data that will facilitate chromosomal mapping and localization of potential oncogenes and tumor suppressors. For example, recent development of innovative technologies, such as digital Karyotyping, array-based comparative genomic hybridization (CHG), and representational oligonucleotide microarray analysis (ROMA) provide molecular platforms that detect DNA copy-number changes at a genome-wide scale with excellent resolution (66). In addition, an automated capillary sequencing platform and other new techniques have become available for large-scale mutational analyses of human cancers. Many research groups have started to apply these new technologies to ovarian cancer with the expectation that they will facilitate the discovery of new tumor-related genes that play a casual role in the development of ovarian cancer.

The pathogenesis, behavior, and clinical management of ovarian borderline tumors, especially, the serous borderline tumors need to be defined. These gaps in the knowledge are largely because of the fact that most studies of SBTs are small, have short follow-up, and are from tertiary care centers. The few population-based studies that have been performed suffer from lack of a uniform pathology review, which results in misclassifi-cation as the diagnoses come from community hospitals where pathologists have limited experience with these tumors. In August 2003, an NIH/NCI workshop on ovarian borderline tumors concluded that much of the confusion and controversy surrounding these tumors were because of lack of population-based studies, in which tumors have been uniformly classified and lack of studies with long-term follow-up (67).

Mortality in patients with SBTs is limited to those with extraovarian disease, but the management of these patients remains controversial. Generally, women with noninvasive implants are followed conservatively whereas those with invasive implants are treated with chemotherapy. Unfortunately, some women with noninvasive implants develop recurrences, and invasive implants typically do not respond to conventional cytotoxic chemotherapy. Accordingly, new types of treatment are necessary for these tumors.

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