Tyrol Prostate Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality

Bartsch, Georg; Horninger, Wolfgang; Klocker, Helmut; Pelzer, Alexandre; Bektic, Jasmin; Oberaigner, Wilhelm; Schennach, Harald; Schäfer, Georg; Frauscher, Ferdinand; Boniol, Mathieu; Severi, Gianluca; Robertson, Chris; Boyle, Peter

doi:10.1111/j.1464-410x.2008.07502.x

Cited by 119 publications

(100 citation statements)

References 43 publications

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“…All men enrolled in the program came from the same "at risk" population, characterized by elevated age-adjusted PSA levels (10,11). Cases were defined as men with biopsy-confirmed prostate cancer, and controls were defined as men with benign prostate biopsy results and no cancer diagnosis on available follow-up data.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, given the strong heritable nature of prostate cancer, we sought to detect clinically-informative prostate cancer risk CNVs in the setting of widespread prostate-specific antigen (PSA) screening, as practiced in the United States (8) and Western Europe (9). To this end, we examined peripheral blood samples from the Tyrol Early Prostate Cancer Detection Program (10,11). This cohort is a populationbased prostate cancer screening program started in 1993 that intended to evaluate the utility of intensive PSA screening in reducing prostate cancer-specific death.…”

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confidence: 99%

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Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Demichelis

Setlur

Banerjee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Copy number variants (CNVs) are a recently recognized class of human germ line polymorphisms and are associated with a variety of human diseases, including cancer. Because of the strong genetic influence on prostate cancer, we sought to identify functionally active CNVs associated with susceptibility of this cancer type. We queried low-frequency biallelic CNVs from 1,903 men of Caucasian origin enrolled in the Tyrol Prostate Specific Antigen Screening Cohort and discovered two CNVs strongly associated with prostate cancer risk. The first risk locus (P = 7.7 × 10 −4 , odds ratio = 2.78) maps to 15q21.3 and overlaps a noncoding enhancer element that contains multiple activator protein 1 (AP-1) transcription factor binding sites. Chromosome conformation capture (Hi-C) data suggested direct cis-interactions with distant genes. The second risk locus (P = 2.6 × 10 −3 , odds ratio = 4.8) maps to the α-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase C (MGAT4C) gene on 12q21.31. In vitro cell-line assays found this gene to significantly modulate cell proliferation and migration in both benign and cancer prostate cells. Furthermore, MGAT4C was significantly overexpressed in metastatic versus localized prostate cancer. These two risk associations were replicated in an independent PSA-screened cohort of 800 men (15q21.3, combined P = 0.006; 12q21.31, combined P = 0.026). These findings establish noncoding and coding germ line CNVs as significant risk factors for prostate cancer susceptibility and implicate their role in disease development and progression.cancer genetics | functionally active DNA loci | cancer predisposition | metabolism | chromosome looping

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Demichelis

Setlur

Banerjee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The clinical samples have been collected within the framework of the Tyrolean prostate cancer early detection program (Bartsch, et al, 2008). Written informed consent was obtained from all patients and the study was approved by the Ethics Committee of the Innsbruck Medical University (Study AM 3174 and amendment 2).…”

Section: Methodsmentioning

confidence: 99%

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

Narisu

Schlick

et al. 2015

Human Mutation

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Genome-wide association studies have identified genomic loci, whose single nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin-IP coupled sequencing and microarray expression profiling in TMPRSS2-ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH), was within a novel putative auxiliary AR binding motif, which is enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of melanophilin in primary prostate tumors was significantly lower in those with the G compared to the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favourable PCa risk profile points out a tumor suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH.

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“…Here, we report an example of the bio-barcode assay performed in human serum, and the results of a pilot study assessing PSA levels in the serum of men who have undergone radical prostatectomy (RRP) for clinically localized prostate cancer (Table 1) (19). Using the bio-barcode assay, we demonstrate the following.…”

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confidence: 99%

Nanoparticle-based bio-barcode assay redefines “undetectable” PSA and biochemical recurrence after radical prostatectomy

Thaxton

Elghanian

Thomas

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We report the development of a previously undescribed gold nanoparticle bio-barcode assay probe for the detection of prostate specific antigen (PSA) at 330 fg/mL, automation of the assay, and the results of a clinical pilot study designed to assess the ability of the assay to detect PSA in the serum of 18 men who have undergone radical prostatectomy for prostate cancer. Due to a lack of sensitivity, available PSA immunoassays are often not capable of detecting PSA in the serum of men after radical prostatectomy. This new biobarcode PSA assay is Ϸ300 times more sensitive than commercial immunoassays. Significantly, with the barcode assay, every patient in this cohort had a measurable serum PSA level after radical prostatectomy. Patients were separated into categories based on PSA levels as a function of time. One group of patients showed low levels of PSA with no significant increase with time and did not recur. Others showed, at some point postprostatectomy, rising PSA levels. The majority recurred. Therefore, this new ultrasensitive assay points to significant possible outcomes: (i) The ability to tell patients, who have undetectable PSA levels with conventional assays, but detectable and nonrising levels with the barcode assay, that their cancer will not recur. (ii) The ability to assign recurrence earlier because of the ability to measure increasing levels of PSA before conventional tools can make such assignments. (iii) The ability to use PSA levels that are not detectable with conventional assays to follow the response of patients to adjuvant or salvage therapies.carcinoma of prostate ͉ prostate specific antigen

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Tyrol Prostate Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality

Cited by 119 publications

References 43 publications

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

Nanoparticle-based bio-barcode assay redefines “undetectable” PSA and biochemical recurrence after radical prostatectomy

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