Evaluating DNA Damage and DNA Repair Capacity as Biomarkers of Nonindolent Prostate Cancer
Abstract
Background: In 2017, it is estimated that 161,000 men in the United States will be diagnosed with prostate cancer (PC). Many of these PCs will exhibit an indolent course, whereas others will behave aggressively and contribute to mortality. While several features of PC can be used to estimate the likelihood that a given cancer will behave in a particular manner, notably the Gleason grade, there is substantial uncertainty with respect to the cancer trajectory in a given individual, which leads to overtreatment. Concurrently, the widespread adoption of active surveillance, while reducing the overtreatment problem, does lead in some circumstances to under-treatment, and there are concerns with missing a window of cure. Defining biomarkers of risk, including risk for developing an aggressive PC and risk for progression, would assist in developing effective screening and management strategies for this very common disease. It is now recognized that PC is comprised of multiple subtypes with distinct genomic features, of which a subset associates with outcomes. Notable among these subtypes are those with defects in DNA repair mechanisms and those with aberrant genomes determined by structural alterations in DNA copy loss and gain, as well as signatures of nucleotide base substitutions that can be classified according to the underlying mutational process. A subset of these processes reflects a heritable predisposition to DNA repair deficiency, and PCs arising in these individuals exhibit aggressive behavior with a high propensity to metastasize. Hypotheses/Objectives: This proposal will test the hypothesis that subtypes of PC, defined by mutational processes and DNA repair deficiency, associate strongly with adverse cancer behavior. The Specific Aims of the project will: (1) determine whether DNA repair signatures and metrics of DNA damage associate with adverse reclassification and adverse pathology in men on active surveillance; (2) determine whether genomic signatures of DNA mutational processes associate with prostate cancer characteristics indicative of non-indolent behavior; and (3) determine whether specific inherited defects in specific genes involved in DNA repair are predictive of adverse prostate cancer outcomes. Impact: This proposal aims to develop accurate approaches capable of distinguishing aggressive from indolent prostate cancer in men newly diagnosed with prostate cancer and, consequently, directly addresses a 2017 Prostate Cancer Research Program (PCRP) Overarching Challenge. Novel aspects of the proposal include the utilizing mutational signatures to define underlying processes that may associate with adverse behavior and exploiting a large multi-institutional active surveillance cohort to provide the power for determining associations with a key mechanism underlying cancer development, DNA repair, and adverse outcomes. The proposal also addresses the FY17 PCRP Focus Area of “Precision Medicine, Screening, and Surveillance.” There is a critical need to identify those individuals that are not suitable for active surveillance, to reassure those that are, and to develop approaches that lessen the over-detection and -treatment problems while preserving the opportunity to cure those cancers that will not be indolent.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810406
Entities
People
- Peter S Nelson
Organizations
- Fred Hutchinson Cancer Center
- United States Army