A number of abnormalities involving cellular proto-oncogenes, including HER-2/neu, 18 AKT2, 19 c-fms, 20 Bcl-2, 21 FGF-3, 22 and met, 23 were described in ovarian carcinomas. Abnormalities involving tumor-suppressor genes such as p53, 24-27 SPARC, 28 and nm23, 29 were also reported. Novel genes were isolated based on their down-regulation in ovarian tumors, and may function as tumor suppressors, 30-32 although their exact roles in ovarian tumorigenesis are still unclear. Data on frequencies of losses of heterozygosity on various chromosomes are extensive, including several complete allelotypes.33-35 In addition, comprehensive cytogenetic analyses of ovarian tumors have been reported.36-39 Specific molecular abnormalities were shown to be associated with disease prognosis21,22,40,41 and specific genes, such as HER-2/neu 42-44 and p53, 45 have been evaluated as potential targets for gene therapy. A comprehensive review of these data are beyond the scope of this chapter, which focuses on molecular genetic studies presented in the context of the ovarian epithelial tumor model described in Fig. 51-2. The intent of this chapter is to provide insights into the molecular genetic changes controlling the different tumor subtypes shown in Fig. 51-1, in order to develop a molecular genetic model for ovarian tumorigenesis similar to what was first achieved with colorectal cancer.46
A genetic model for sporadic (nonfamilial) ovarian epithelial tumor development.
The complexity of molecular genetic changes present in ovarian carcinomas clearly increases with increasing tumor histologic grades.35,37,47,48 This observation is in agreement with classical tumor progression theories.49 Grades of ovarian carcinomas, however, are not only a function of the mere number of molecular genetic abnormalities present in a given tumor genome as specific molecular abnormalities appear strongly associated with high histologic grades.35,37,47,48,50,51 Thus, whereas losses of heterozygosity affecting certain chromosomes, such as 6q, 17p, and 17q, appear frequently in ovarian tumors of all histologic grades, 35 losses in chromosome 13 are frequent only in those of high histologic grades.50,51 It may be that the gene(s) targeted by losses of heterozygosity in chromosome 13 control(s) a different cellular pathway associated perhaps with differentiation or other determinants of tumor grade, but not with cell-cycle regulation. Proof of this hypothesis awaits identification and characterization of the gene(s) targeted by these losses of heterozygosity.
Recent data35,37 also provide insights into the molecular genetic differences distinguishing ovarian carcinomas from the noninvasive and nonmetastatic ovarian epithelial tumors (Fig. 51-2). Examination of the distribution and frequencies of losses of heterozygosity in these various tumor subtypes showed that such losses, which are frequent in ovarian carcinomas, are rare in the biologically less aggressive ovarian epithelial tumors (with the exception of losses affecting the X chromosome in LMP tumors discussed below).35 Thus, the underlying defects responsible for loss of heterozygosity usually result in malignancy, implying that tumor-suppressor gene inactivation, which is an important consequence of such losses, is not a feature of cystadenoma or LMP tumor development.35 Other published molecular genetic differences between the different subtypes of ovarian tumors mentioned in Fig. 51-2 include the presence of p53 mutations, 27,52 which is strongly associated with malignant tumors, and changes in DNA methylation, 53 which are associated with both LMP tumors and carcinomas, but not with cystadenomas. Telomerase, an enzyme necessary for unlimited cell growth, is usually not detected in cystadenomas, whereas it is expressed in most LMP tumors and carcinomas.54
The only exception to the rarity of losses of heterozygosity in LMP tumors are losses affecting the X chromosome, which are present in about 50 percent of cases.35 The target(s) of the allelic losses involving this chromosome in LMP tumors is not known, although the candidate chromosomal region was recently narrowed down considerably.55 That the reduced allele invariably affects the inactive copy of this chromosome suggests that the targeted gene(s) escapes X inactivation. This suggestion is attractive because individuals born with a single X chromosome (Turner syndrome)56 show abnormal ovarian development (gonadal dysgenesis). Thus, the presence of the inactive X chromosome is necessary for normal ovarian development and it is conceivable that abnormalities in the same gene during adult life may lead to tumorigenesis. The X chromosome is also thought to be important for the establishment of in vitro immortality, 57,58 and was recently implicated in the development of prostate cancer.59