Developing a PTEN-ERG Signature to Improve Molecular Risk Stratification in Prostate Cancer
Abstract
Objective and Rationale: Prostate cancer is a clinically and genetically heterogeneous disease, and the development of a classification based on the molecular characteristics is critical to distinguish lethal from indolent tumors and minimize disease overtreatment. Genomic alterations of the PTEN and ERG genes are among the most common in prostate cancer, and there is an enormous interest in exploiting these alterations in routine risk assessment. We found that the loss of PTEN is associated with prostate cancer death most strongly in the patients whose tumors do not carry a rearrangement of the ERG gene. This suggests that the absence of ERG strengthens the association of PTEN loss with prostate cancer lethal progression, contradicting findings from mouse laboratory models. Recent technological advances have enabled extraordinary insight into alterations in gene expression patterns and molecular alterations that occur in prostate cancer. Importantly, novel technologies are now making these technological advances applicable to routine pathological specimens collected at diagnosis or surgery, which until recently could not be comprehensively studied. Likewise, these technologies have enabled the development of clinical assays that provide patients with estimates of the risk that their prostate cancer will behave aggressively. Despite these advances and the fact that PTEN and ERG molecular classification is widely accessible and relatively inexpensive, our understanding of the interaction between these genes during prostate cancer progression remains very limited, and we still do not have a molecular signature of PTEN and ERG loss in prostate cancer. To address these issues, we have formed a collaborative, multidisciplinary team, led by a urologic pathologist and computational biologist with expertise in prostate cancer molecular pathology and cancer genomics. Our team includes clinicians treating prostate cancer, as well as an industry collaborator focused on improving prognostication in the disease. Collectively, our objective is to perform a comprehensive molecular assessment of well-annotated prostate cancers in relation to PTEN and ERG status using existing and novel data. We will specifically confirm that the tumors with loss of PTEN and lacking ERG rearrangement are among the most aggressive. We will then characterize the expression profiles associated with PTEN and ERG alterations, which means that we will identify the genes that are "turned on" and "turned off" in response to changes in PTEN and ERG. Lastly, we will determine whether these expression profiles can improve the way we stratify prostate cancer patients into different risk groups. Applicability: Findings from our proposed research would have both immediate and long-term clinical and translational research applicability. First, by analyzing several large clinical cohorts from multiple institutions using an optimized assay for PTEN and ERG detection, we will be able confirm the performance of these biomarkers in classifying into risk groups a large set of patients. In addition, through partnering with industry and utilizing genomic data from a commercially available prognostic assay, we also will be able to evaluate how well our PTEN/ERG molecular signatures correlate with risk of developing a lethal disease in comparison to the currently available prognostic assays in a large collection of patients. Furthermore, with our comprehensive approach, we expect to identify the molecular alterations that are responsible for the different clinical and biological behavior of tumors based on PTEN and ERG status. These alterations can then be functionally studied in future work to determine how they contribute to prostate cancer aggressiveness and whether they may ultimately serve as therapeutic vulnerabilities. Importantly, we expect that results from our proposed studies of PTEN/ERG molecular signatures will benefit all men affected by prosta
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610737
Entities
People
- Tamara L Lotan
Organizations
- Johns Hopkins University
- United States Army