Prostate cancer (CaP) is diagnosed in ~ 230,000 men annually making it the most commonly diagnosed non-cutaneous cancer among American men. Moreover, approximately 30,000 men die each year from metastasis, thus there is an urgent need to understand the mechanism of metastasis. We have analyzed ~ 130 prostate tumors using array comparative genomic hybridization (aCGH). These tumors include those from 64 men at intermediate to high-risk of progression with up to 16 years clinical follow-up. Half the patients progressed biochemically (PSA) and half did not. Included amongst the tumors that recurred are 12 primary tumors that later metastasized to bone. In an independent study, the genomes of 19 organ metastases were analyzed using aCGH. Copy number profiles from the 12 primary tumors that metastasized and 19 metastases were used to detect signatures of metastasis in primary tumors. These events occur as relatively rare events in primary tumors but manifest as highly recurrent amplifications and deletions in the metastases. BAG clones at the 39 loci were required to detect the signatures of metastasis. We call these loci the genomic evaluators of metastatic CaP (GEMCaP). These findings have far reaching and indeed paradigm shifting implications for the diagnosis and treatment of CaP. We will validate the GEMCaP loci in a blinded study and compare their ability to predict recurrence to the UCSF-CAPRA and Kattan risk assessment nomograms. To focus our studies on the highest value loci we will employ comparative oncogenomics and integrate GEMCaP data with aCGH data from brain, breast, and ovarian tumors. Thus, we will test the hypothesis that markers of progression and metastasis identified using CaP metastases can predict the clinical behavior of independent primary tumor types and, moreover, may lead to broad spectrum drug targets with associated predictive biomarkers. A limited number of GEMCaP loci aberrant in multiple tumors types will be functionally analyzed in vitro and in vivo. This type of approach is essential if potential therapies discovered in academic laboratories are to be advanced to clinical oncology through the pharmaceutical industry, with the goal of eliminating death and suffering from cancer by 2015 as challenged by Dr. von Eschenbach.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Biomarkers Study Section (CBSS)
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Tricoli, James
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Heselmeyer-Haddad, Kerstin M; Berroa Garcia, Lissa Y; Bradley, Amanda et al. (2014) Single-cell genetic analysis reveals insights into clonal development of prostate cancers and indicates loss of PTEN as a marker of poor prognosis. Am J Pathol 184:2671-86
Paris, Pamela L; Weinberg, Vivian; Albo, Giancarlo et al. (2010) A group of genome-based biomarkers that add to a Kattan nomogram for predicting progression in men with high-risk prostate cancer. Clin Cancer Res 16:195-202
Paris, P L; Sridharan, S; Hittelman, A B et al. (2009) An oncogenic role for the multiple endocrine neoplasia type 1 gene in prostate cancer. Prostate Cancer Prostatic Dis 12:184-91
Paris, Pamela L; Sridharan, Shivaranjani; Scheffer, Alicia et al. (2007) High resolution oligonucleotide CGH using DNA from archived prostate tissue. Prostate 67:1447-55