Genetic analysis of solid tumours using DNA or cDNA expression microarrays may enable individualized treatment based on the profiles of genetic changes that are identified from each patient. This could result in better response to adjuvant chemotherapy and, consequently, improved clinical outcome. So far, most research studies that have tested the efficacy of such an approach have sampled only single areas of neoplastic tissue from tumours; this assumes that the genetic profile within solid tumours is homogeneous throughout. The aim of this study was to evaluate the extent of genetic intra-tumour heterogeneity (ITH) within a series of epithelial ovarian cancers. Several different regions (five to eight regions) of tumour tissue from 16 grade 3, serous epithelial ovarian cancers were analysed for genetic alterations using a combination of microsatellite analysis and single nucleotide polymorphism (SNP) analysis, in order to establish the extent of ITH. Maximum parsimony tree analysis was applied to the genetic data from each tumour to evaluate the clonal relationship between different regions within tumours. Extensive ITH was identified within all ovarian cancers using both microsatellite and SNP analysis. Evolutionary analysis of microsatellite data suggested that the origin of all tumours was monoclonal, but that subsequent clonal divergence created mixed populations of genetically distinct cells within the tumour. SNP analysis suggested that ITH was not restricted to random genetic changes, but affected genes that have an important functional role in ovarian cancer development. The frequent occurrence of ITH within epithelial ovarian cancers may have implications for the interpretation of genetic data generated from emerging technologies such as DNA and mRNA expression microarrays, and their use in the clinical management of patients with ovarian cancer. The basis of genetic ITH and the possible implications for molecular approaches to clinical diagnosis of ovarian cancers may apply to other tumour types.

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...

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