Prognostication and clinical management of prostate cancer (PCA) is one the most complex an controversial issues in contemporary oncology. Our overarching goal is to develop tissue based molecula tests to distinguish indolent from aggressive PCA prior to treatment. Our proposal will address several critica issues related to the development of a clinically relevant molecular signature of PCA: (1) We use PC specific death as the clinical endpoint;(2) We will employ 3 well defined patient populations from Swede with long term and complete clinical follow up;(3) We use tumor enriching methods such as laser captur microdissection (LCM) due to the cellular heterogeneity of PCA These guiding principles have been organized into 3 Specific Aims:
In Aim 1, we use 10OK single nucleotid polymorphism (SNP) arrays for the detection of Loss of Heterozygosity (LOH), homozygous deletions an gene amplification events to generate genome-wide genetic maps at a resolution of 9Kb. Combining thi molecular signature data with clinical data on PCA biopsy samples from 96 consecutive frozen samples fro men diagnosed in Orebro, Sweden with clinically localized PCA of whom 40 died of PCA and 30 of othe causes, we will develop a molecular signature to distinguish aggressive from indolent PCA.
In Aim 2, we tes and validate this molecular profile using a bead-based nanotechnology to assess for somatic alterations i the DNA that can be applied on formalin-fixed paraffin embedded samples from the nationwide cohort o prostatectomies in Sweden (n=600) and two Watchful Waiting cohorts (n=620) with a projected 200 and 12 PCA specific deaths, respectively.
In Aim 3, we will employ tissue microarrays from the Swedis Prostatectomy and the Watchful Waiting cohorts and evaluate combinations of biomarkers by quantitativ analysis of immunohistochemistry, immunofluorescence (AQUA), in situ hybridization (ISH)or fluorescenc in situ hybridization(FISH) We expect to develop in situ tests that will be transportable to other laboratories for clinical validation. At th conclusion of this proposal, we expect to have refined and fully validated molecular predictors of PCA deat as well as indolent PCA that is appropriate for further clinical development.
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