The clonal evolution of metastases from primary serous epithelial ovarian cancers

Abstract

Several models of evolution from primary cancers to metastases have been proposed; but the most widely accepted is the clonal evolution model proposed for colorectal cancer in which tumors develop by a process of linear clonal evolution driven by the accumulation of somatic genetic alterations. Various other models of cancer progression and metastasis have been proposed, including parallel evolution and the same gene model. The aim of this study was to investigate the evolution of metastases from primary cancer in 22 patients diagnosed with high-grade serous epithelial ovarian cancer. We established somatic genetic profiles based on the pattern of loss of heterozygosity, in several different regions of tumor tissue within the primary tumor and metastatic deposits from each case. Maximum parsimony tree analysis was used to examine the evolutionary relationship between the primary and metastatic samples for each patient. In addition, we investigated the extent of genetic heterogeneity within and between metastatic tumors compared with primary ovarian tumors. Our data suggest that most, if not all, metastases are clonally related to the primary tumors. However, the data oppose a single model of linear-clonal evolution whereby a late stage clone within the primary tumor acquires additional genetic changes that enable metastatic progression. Instead, the data support a model in which primary ovarian cancers have a common clonal origin, but become polyclonal, with different clones at both early and late stages of genetic divergence acquiring the ability to progress to metastasis. ' 2008 Wiley-Liss, Inc.Key words: ovarian cancer; genetic analysis; metastasis; clonal evolution; maximum parsimony; high-grade serous histology Genetic studies of colorectal cancer led Fearon and Vogelstein to propose that tumors develop by a process of clonal expansion driven by the accumulation of somatic genetic alterations, and this has become the most widely accepted model of tumor development.1-3 The final step in this process is progression to metastasis, when 1 or more clonal populations of cancer cells have acquired sufficient genetic and functional changes to enable secondary tumor formation.Epithelial cancers represent 90% of all malignant ovarian tumors; but the underlying genetic basis of ovarian tumor development remains poorly understood. This is partly because epithelial ovarian cancer is an extremely heterogeneous disease consisting of a wide spectrum of histological subtypes. There is mounting evidence that different molecular mechanisms are involved in the development of different ovarian tumor subtypes. Recent studies have also suggested that there is extensive genetic heterogeneity within ovarian tumors, which may hinder a better understanding of cancer development. Primary ovarian cancers tend to spread, at first, within the peritoneal cavity and the omentum, and are frequently associated with ascites, a fluid rich in growth factors and tumor cells disseminated from the primary cancer that fills the peritoneum. Tumor sp...

Treatment-Related Protein Biomarker Expression Differs between Primary and Recurrent Ovarian Carcinomas

“…In addition to the differences noted in recurrences compared with primary specimens, we found that expression of some of the markers (i.e., PGP as well as EGFR, BCRP, RRM1, and TOPO1) also differed in recurrent specimens taken from the same patient at different times during the course of disease. These differences may reflect alterations in gene expression programs that are dependent on the site of the tumor as suggested by genomic profiling studies of primary ovarian and omental lesions (22) or the genotypic divergence observed in multiple metastases derived from matched primary tumors obtained from untreated patients (23). In our study, the recurrences tested were obtained from patients who had received 1 to 5 prior therapies, so it is also possible that the chemotherapy regimen received in the intervening time period either induced/repressed expression of these proteins or selected for a preexisting tumor cell population with an altered expression of that marker.…”

Ovarian Cancer Development and Metastasis

“…The alternative explanation is that most of the metastatic potential of the ovarian carcinoma cells already exists in the genetic changes present in the primary tumor and, therefore, it depends less on metastasis related selection pressure. This hypothesis was further refined by an elegant study from Khalique et al 95 who evaluated clonal evolution between primary ovarian tumors and their metastasis using parsimony tree analysis, a software usually used to understand the evolution of animal species. They found that all metastases closely resemble the primary tumor and that different cancer clones within the primary tumor can give rise to metastasis.…”

Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

“…Investigations of the transcriptional profile by microchip analysis (23,24), chromosomal constitution after genomic hybridization (25,26), and parsimony tree analysis (27) of paired ovarian carcinomas and their corresponding metastases concluded that tumor cells from both locations exhibited the same pattern of expression. These findings are in agreement with the hypothesis that ovarian cancer metastases are generated by passive transport of tumor cells with ascites.…”