1. Comprehensive Gene Expression Analysis of Prostate Cancer Reveals Distinct Transcriptional Programs Associated With Metastatic Disease Kevin Paiz-Ramirez Janelle N. Ruiz Biology 398.01 Department of Biology Loyola Marymount University April 11, 2010 Eva, La Tullippe, Jaya Satagopan, Alex Smith, Howard Scher, Peter Scardino, Victor Reuter, William Gerald. Department of Pathology

2. Outline I.Differences in gene expression profiles between progressive and non-progressive tumors can explain the mechanism of disease. II.Microarray analysis was used to determine differential gene expression III.Differentially expressed genes between metastatic and primary tumors were found: I.Cell Cycle Regulation II.Mitosis III.Signaling IV.DNA Replication IV.Metastatic tumors had higher proliferation index than primary tumors. V.Both previously-identified and novel differentially expressed genes were identified.

3. Importance of Investigating Gene Expression Profiles of Prostate Cancer Tumors Carcinoma of the prostate is the most common cancer in the United States Tumors can be classified as being either metastasized or localized Development of metastatic disease leads to death. Improving tumor classification and therapy can be achieved by identifying –Genes –Gene expression profiles –Biological pathways

4. Genome Wide Expression Analysis of Primary and Metastatic Prostate Cancers Tissues samples were taken from: –3 Non cancerous Patients –23 Primary Prostate Cancer Patients –9 Metastatic Prostate cancer Patients Collected as biopsies from 1993-1999 Analysis was preformed with Affymetrix chips Within chip and between chip normalization was carried out by multiplying expression values such that the average expression was 2500 They considered genes to be differentially expressed if they differed by 3 fold between two groups They took the Log 10 of the ratio of the means.

5. Differences in Clinical and Pathological Features Between Primary and Metastatic Tumors

6. Clustering Shows That Primary Tumors Have A Different Expression Profile Than The Metastatic Tumors

7. Genes Involved in Cell Cycle Regulation, DNA Replication and Repair, and Mitosis Were Highly Differentially Expressed in Metastatic Tumors

8. Genes Involved in Signaling and Signal Transduction Were Differentially Expressed in Metastatic Tumors

9. Genes Involved in Transcriptional Regulation and Cell Adhesion Were Highly Differentially Expressed in Metastatic Tumors

10. Metastatic Tumors Present Higher Proliferation Index Than Primary Tumors

12. Quantitative RT-PCR Confirms Relative Expression Values Observed From Microarray Experiment

13. Microarray Data Reveals Both Previously-Identified and Novel Differentially Expressed Genes Between Primary and Metastatic Tumors Previous studies have revealed similar patterns of gene expression. Differentially expressed genes of functional pathways previously implicated in aggressive disease Analysis reveled hundreds of poorly characterized gene clusters that likely represent novel genes of unknown function –Biological activity of these genes can be inferred from other known genes with shared expression patterns

14. Determining Function of Unknown Genes May Identify Potential Therapeutic Targets Few prior studies have used high-throughput gene expression analysis to study prostate cancer metastasis Some of genes differentially expressed may identity critical functional pathways: –Example: MYBL2 may signify critical component of cell cycle regulation in metastatic cancer Further studies would determine the function of unknown genes and identify potential therapeutic targets for treatment.

15. References LaTulippe E, Satagopan J, Smith A, Scher H, Scardino P, Reuter V, and Gerald L. Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res 2002 Aug 1; 62(15) 4499-506.