Variation in gene expression patterns in effusions and primary tumors from serous ovarian cancer patients

BACKGROUND: While numerous studies have characterized primary ovarian tumors, little information is available regarding expression patterns of metastatic sites of this cancer. To define sets of genes that distinguish primary and metastatic ovarian tumors, we used cDNA microarrays to characterize global gene expression patterns in 38 effusions (28 peritoneal, 10 pleural) and 8 corresponding primary ovarian tumors, and searched for associations between expression patterns and clinical parameters. RESULTS: We observed multidimensional variation in expression patterns among the cancers. Coordinate variation in expression of genes from two chromosomal regions, 8q and 19q, was seen in subsets of the cancers indicating possible amplifications in these regions. A set of 112 unique genes of known function was differentially expressed between primary tumors and effusions using supervised analysis. Relatively few differences were seen between effusions isolated from the pleural and peritoneal cavities or between effusions from patients diagnosed with stage III and stage IV cancers. A set of 84 unique genes was identified that distinguished high from lower grade ovarian cancers. The results were corroborated using immunocytochemistry, mRNA in situ hybridization, and immunoblotting. CONCLUSION: The extensive variation in expression patterns observed underscores the molecular heterogeneity of ovarian cancer, but suggests a similar molecular profile for ovarian carcinoma cells in serosal cavities

High levels of genomic aberrations in serous ovarian cancers are associated with better survival

Martin K Oehler is a member of the Australian Ovarian Cancer Study GroupGenomic instability and copy number alterations in cancer are generally associated with poor prognosis; however, recent studies have suggested that extreme levels of genomic aberrations may be beneficial for the survival outcome for patients with specific tumour types. We investigated the extent of genomic instability in predominantly high-grade serous ovarian cancers (SOC) using two independent datasets, generated in Norway (n = 74) and Australia (n = 70), respectively. Genomic instability was quantified by the Total Aberration Index (TAI), a measure of the abundance and genomic size of copy number changes in a tumour. In the Norwegian cohort, patients with TAI above the median revealed significantly prolonged overall survival (p<0.001) and progression-free survival (p<0.05). In the Australian cohort, patients with above median TAI showed prolonged overall survival (p<0.05) and moderately, but not significantly, prolonged progression-free survival. Results were confirmed by univariate and multivariate Cox regression analyses with TAI as a continuous variable. Our results provide further evidence supporting an association between high level of genomic instability and prolonged survival of high-grade SOC patients, possibly as disturbed genome integrity may lead to increased sensitivity to chemotherapeutic agents.Lars O. Baumbusch, Åslaug Helland, Yun Wang, Knut Liestøl, Marci E. Schaner, Ruth Holm, Dariush Etemadmoghadam, Kathryn Alsop, Pat Brown, Australian Ovarian Cancer Study Group, Gillian Mitchell, Sian Fereday, Anna DeFazio, David D. L. Bowtell, Gunnar B. Kristensen, Ole Christian Lingjærde, Anne-Lise Børresen-Dal

Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers

BACKGROUND: Inadequate oxygen (hypoxia) triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF), plays a central role in the hypoxia response; its activity is regulated by the oxygen-dependent degradation of the HIF-1α protein. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia among different cell types or how this variation might relate to tissue- and cell-specific diseases. METHODS AND FINDINGS: We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1α RNA in renal cells, and it could be diminished by reducing HIF-1α expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use. CONCLUSIONS: The transcriptional response to hypoxia varies among human cells. Some of this variation is traceable to variation in expression of the HIF1A gene. A gene-expression signature of the cellular response to hypoxia is associated with a significantly poorer prognosis in breast and ovarian cancer

Functional Characterization of a Human Purine-Selective, Na ϩ -Dependent Nucleoside Transporter (hSPNT1) in a Mammalian Expression System 1

ABSTRACT Nucleosides and nucleoside analogs are actively transported in the human kidney. With the recent cloning of a purine-selective, Na ϩ -dependent, nucleoside transporter (hSPNT1, also termed hCNT2) from human kidney, it is now possible to study the interaction of nucleosides and nucleoside analogs with this transport protein and gain a more detailed knowledge of the underlying mechanisms of nucleoside transport in the human kidney. In this study we examined the substrate selectivity of hSPNT1 for nucleosides and nucleoside analogs. We determined that the naturally occurring nucleosides adenosine, inosine, and uridine are substrates for this carrier, whereas thymidine is not. The nucleoside analogs (0.5 mM) 2Ј,3Ј-dideoxyadenosine; 2Ј,3Ј-dideoxyinosine; and 2-chloro-2Јdeoxyadenosine (2CdA), significantly inhibited the uptake of [

Frequency of copy number changes in serous ovarian carcinomas of two independent cohorts.

<p>The frequencies of copy number alterations in serous ovarian cancers of two independent cohorts from Norway and Australia are illustrated. Regions with copy number gains are marked in red and regions with copy number losses are marked in green, respectively. (a) The frequency of copy number changes of 74 serous ovarian tumours of the Norwegian cohort were determined using 42k cDNA arrays. Several high frequency peaks are visible, including gains at regions on chromosome arms 1q, 3q, 8q, and 20q, and losses on chromosome arms 4q, 5q, 6 p, 8 p, 13, 16q, 18q, and the whole of the X chromosome. (b) The frequency of aberrations of 70 ovarian tumour samples of the Australian cohort, as measured by 50 k SNP Affymetrix arrays. All high frequency peaks of the Norwegian cohort are also identified in the Australian cohort, although some additional peaks appear in the Australian data, e.g. gains in 1 p and losses on chromosome arms 17 p and 22q. The two data sets show high consistency in the aberration pattern, despite differences in populations and analysis platforms (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054356#pone-0054356-g003" target="_blank">Figure 3</a>).</p

Gene Expression Patterns in Ovarian Carcinomas

We used DNA microarrays to characterize the global gene expression patterns in surface epithelial cancers of the ovary. We identified groups of genes that distinguished the clear cell subtype from other ovarian carcinomas, grade I and II from grade III serous papillary carcinomas, and ovarian from breast carcinomas. Six clear cell carcinomas were distinguished from 36 other ovarian carcinomas (predominantly serous papillary) based on their gene expression patterns. The differences may yield insights into the worse prognosis and therapeutic resistance associated with clear cell carcinomas. A comparison of the gene expression patterns in the ovarian cancers to published data of gene expression in breast cancers revealed a large number of differentially expressed genes. We identified a group of 62 genes that correctly classified all 125 breast and ovarian cancer specimens. Among the best discriminators more highly expressed in the ovarian carcinomas were PAX8 (paired box gene 8), mesothelin, and ephrin-B1 (EFNB1). Although estrogen receptor was expressed in both the ovarian and breast cancers, genes that are coregulated with the estrogen receptor in breast cancers, including GATA-3, LIV-1, and X-box binding protein 1, did not show a similar pattern of coexpression in the ovarian cancers

Examples of genomic profiles with low (left) and high (right) median Total Aberration Index (TAI).

<p>(a.) Examples from the Norwegian and (b.) from the Australian cohort. The log2-transformed copy numbers of the chromosomes 1 to 23 are illustrated. The median was 0.135 for the Norwegian and 0.242 for the Australian cohort.</p