Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

Psychology and aggression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68264/2/10.1177_002200275900300301.pd

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry–specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13–7.22) and 33.41 (95% CI = 10.86–102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17–25%) for TA heterozygotes and 38% (95% CI = 13–65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. Patient summary: We found that rs72725854, an African ancestry–specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening. © 2020 The AuthorsThe African ancestry–specific prostate cancer risk variant at 8q24, rs72725854, is enriched in men diagnosed at younger ages and men with a prostate cancer family history. Carriers of this risk allele would benefit from regular and earlier prostate cancer screening

P-cadherin is a basal cell-specific epithelial marker that is not expressed in prostate cancer

Contains fulltext : 24613___.PDF (publisher's version ) (Open Access

The role of genetic markers in the management of prostate cancer.

Item does not contain fulltextCONTEXT: Despite widespread screening for prostate cancer (PCa) and major advances in the treatment of metastatic disease, PCa remains the second most common cause of cancer death for men in the Western world. In addition, the use of prostate-specific antigen testing has led to the diagnosis of many potentially indolent cancers, and aggressive treatment of these cancers has caused significant morbidity without clinical benefit in many cases. The recent discoveries of inherited and acquired genetic markers associated with PCa initiation and progression provide an opportunity to apply these findings to guide clinical decision making. OBJECTIVE: In this review, we discuss the potential use of genetic markers to better define groups of men at high risk of developing PCa, to improve screening techniques, to discriminate indolent versus aggressive disease, and to improve therapeutic strategies in patients with advanced disease. EVIDENCE ACQUISITION: PubMed-based literature searches and abstracts through January 2012 provided the basis for this literature review. We also examined secondary sources from reference lists of retrieved articles and data presented at recent congresses. Cited review articles are only from the years 2007-2012, favoring more recent discussions because of the rapidly changing field. Original research articles were curated based on favoring large sample sizes, independent validation, frequent citations, and basic science directly related to potentially clinically relevant prognostic or predictive markers. In addition, all authors on the manuscript evaluated and interpreted the data acquired. EVIDENCE SYNTHESIS: We address the use of inherited genetic variants to assess risk of PCa development, risk of advanced disease, and duration of response to hormonal therapies. The potential for using urine measurements such as prostate cancer antigen 3 (PCA3) RNA and the transmembrane protease, serine 2 v-ets erythroblastosis virus E26 oncogene homolog (avian) (TMPRSS2-ERG) gene fusion to aid screening is discussed. Multiple groups have developed gene expression signatures from primary prostate tumors correlating with poor prognosis, and attempts to improve and standardize these signatures as diagnostic tests are presented. Massive sequencing efforts are underway to define important somatic genetic alterations (amplifications, deletions, point mutations, translocations) in PCa, and these alterations hold great promise as prognostic markers and for predicting response to therapy. We provide a rationale for assessing genetic markers in metastatic disease for guiding choice of therapy and for stratifying patients in clinical trials, and discuss challenges in clinical trial design incorporating the use of these markers. CONCLUSIONS: The use of genetic markers has the potential to aid disease screening, improve prognostic discrimination, and prediction of response to treatment. However, most markers have not been prospectively validated for providing useful prognostic or predictive information or improvement upon clinicopathologic parameters already in use. Significant efforts are underway to develop these research findings into clinically useful diagnostic tests in order to improve clinical decision making.1 oktober 201

DD3: A new prostate-specific gene, highly overexpressed in prostate cancer

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Molecular prostate cancer pathology: current issues and achievements.

Recent developments in the field of molecular techniques have provided new tools that have led to the discovery of many new promising biomarkers for prostate cancer. These biomarkers may be instrumental in the development of new tests that will have a high specificity for the diagnosis and prognosis of prostate cancer. A biomarker is defined as a molecular test that provides additional information to currently available clinical and pathological tests. Biomarkers should be reproducible (both within and between institutes) and have an impact on clinical management. For diagnostic purposes it is important that potential biomarkers are tested in terms of tissue specificity and their discrimination potential between prostate cancer, normal prostate and benign prostatic hyperplasia. The results of (multiple) biomarker-based assays may enhance the specificity of cancer detection. There is an urgent need for molecular prognostic biomarkers for predicting the biological behavior and outcome of cancer

Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer

Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of androgen receptor signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splice variants (AR-Vs) lack the androgen receptor ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies including CRPC therapies such as abiraterone and MDV3100. While the canonical full-length androgen receptor (AR-FL) and AR-Vs are both increased in CRPCs, their expression regulation, associated transcriptional programs, and functional relationships have not been dissected. In this study, we show that suppression of ligand-mediated AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPCs. Importantly, treatment-induced AR-Vs activated a distinct expression signature enriched for cell-cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppressed the AR-Vs signature and activated expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 or abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, paralleled increased expression of the androgen receptor–driven cell-cycle gene UBE2C. Expression of AR-V7, but not AR-FL, was positively correlated with UBE2C in clinical CRPC specimens. Together, our findings support an adaptive shift toward AR-V–mediated signaling in a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapy