No Detection of XMRV in Blood Samples and Tissue Sections from Prostate Cancer Patients in Northern Europe

BACKGROUND: We recently published the rare detection of xenotropic murine leukemia virus-related virus (XMRV) (1/105) in prostate cancer (PCA) tissue of patients in Northern Europe by PCR. The controversial discussion about the virus being detected in PCA tissue, blood samples from patients suffering from chronic fatigue syndrome (CFS), as well as from a significant number of healthy controls prompted us to deepen our studies about detection of XMRV infection applying different detection methods (PCR, cocultivation and immunohistochemistry [IHC]). METHODOLOGY/PRINCIPAL FINDINGS: Peripheral blood mononuclear cells (PBMCs) from 92 PCA and 7 healthy controls were isolated, PHA activated and cocultivated with LNCaP cells for up to 8 weeks. Supernatant of these cells was applied to a reporter cell line, DERSE-iGFP. Furthermore, the PBMCs and cocultivated LNCaP cells were tested for the presence of XMRV by PCR as well as Western Blot analysis. While all PCR amplifications and Western Blot analyses were negative for signs of XMRV infection, DERSE-iGFP cells displayed isolated GFP positive cells in three cases. In all three cases XMRV presence could not be confirmed by PCR technology. In addition, we performed XMRV specific IHC on PCA tissue sections. Whole tissue sections (n = 20), as well as tissue microarrays (TMA) including 50 benign prostate hyperplasia (BPH), 50 low grade and 50 high grade PCA sections and TMAs including breast cancer, colon cancer and normal tissues were stained with two XMRV specific antisera. XMRV protein expression was not detected in any cancer sections included. One BPH tissue displayed XMRV specific protein expression in random isolated basal cells. CONCLUSION: We were unable to conclusively detect XMRV in the blood from PCA patients or from healthy controls and there is no conclusive evidence of XMRV protein expression in PCA, breast cancer and colon cancer tissue sections tested by IHC staining

VPRBP functions downstream of the androgen receptor and OGT to restrict p53 activation in prostate cancer

Androgen receptor (AR) is a major driver of prostate cancer initiation and progression. O-GlcNAc transferase (OGT), the enzyme that catalyzes the covalent addition of UDP-N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of proteins, is often highly expressed in prostate cancer with its expression correlated with high Gleason score. In this study, we have identified an AR and OGT coregulated factor, Vpr (HIV-1) binding protein (VPRBP) also known as DDB1 and CUL4 Associated Factor 1 (DCAF1). We show that VPRBP is regulated by the AR at the transcript level, and stabilized by OGT at the protein level. VPRBP knockdown in prostate cancer cells led to a significant decrease in cell proliferation, p53 stabilization, nucleolar fragmentation, and increased p53 recruitment to the chromatin. In human prostate tumor samples, VPRBP protein overexpression correlated with AR amplification, OGT overexpression, a shorter time to postoperative biochemical progression and poor clinical outcome. In clinical transcriptomic data, VPRBP expression was positively correlated with the AR and also with AR activity gene signatures.ImplicationsIn conclusion, we have shown that VPRBP/DCAF1 promotes prostate cancer cell proliferation by restraining p53 activation under the influence of the AR and OGT

Sex differences in oncogenic mutational processes.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Successful Reversal of Bradycardia and Dyspnea With Aminophylline After Ticagrelor Load

A 69-year-old male underwent elective percutaneous coronary intervention requiring placement of a drug-eluting stent to the first obtuse marginal artery. Four hours following the administration of a ticagrelor loading dose, he developed dyspnea and sinus pauses. Aminophylline was administered and resulted in immediate and sustained symptom resolution. Ticagrelor has been associated with dyspnea and bradyarrhythmias, both attributed to increased adenosine exposure. Ticagrelor inhibits reuptake of intracellular adenosine. Adenosine antagonists aminophylline and theophylline have been utilized to reverse the effects of adenosine and may relieve adenosine-mediated adverse effects induced by ticagrelor therapy. Aminophylline may be considered for reversal of dyspnea and bradyarrhythmia associated with ticagrelor therapy through alterations in adenosine exposure.</jats:p

Abstract 4353: Improved prediction of prostate cancer prognosis by using a multiparametric molecular classifier

Abstract Background: Because no single molecular marker have proven to be sufficiently powerful for routine estimation of prostate cancer prognosis as to yet, it is hoped that the combined analysis of multiple markers will allow for distinguishing between indolent and aggressive forms of prostate cancer. In fact, first generation commercial multiparametric test assays show promising results. We hypothesized that such tests may be further optimized. Design: A tissue microarray (TMA) containing 0.6 mm tissue cores from more than 12,000 prostate cancer patients with long-term follow-up data was analyzed with more than 100 molecular markers by immunohistochemistry or FISH. Markers with strong and independent prognostic value in uni- and multivariate analyses were combined to obtain panels of markers that yield additional prognostic information beyond the standard parameters (including pre-operative PSA, Gleason grade, tumor stage, nodal stage) in ROC analysis. For this purpose, a simple score (0-10 points) was build based on the number and type of adverse features per tumor. Results: Markers with strong independent prognostic relevance included deletions of 6q15 and PTEN, overexpression of EZH2, TUBB3, and nuclear accumulation of p53, indicating dominant-negative TP53 gene mutation. A total of 5,129 cancers harbored none of these alterations (score 0) and showed the best prognosis in a Kaplan-Meier plot using biochemical recurrence as the study endpoint. The worst prognosis was found for 610 tumors harboring ≥8 (score 8-10) of these alterations, while an intermediate prognosis with decreasing time to recurrence was found for cancers with scores 1-2 (n = 2,418), 3-4 (n = 1,367) and 5-7 (n = 1038). The differences between the groups were high significant (p&amp;lt;0.0001). The 5 genes classifier provided prognostic information independent from PSA, Gleason, stage, and nodal stage (p&amp;lt;0.0001). Conclusion: Multiparametric classifiers have a high potential to improve the predictive accuracy of current models using established clinic-pathological models. Analyses of very large sets of patient tissues are instrumental to identify the best candidates for such molecular marker panels. It is likely, that continued analysis of our TMA will identify even better marker panels than the current 5 genes classifier. Citation Format: Maria Christina Tsourlakis, Martina Kluth, Thorsten Schlomm, Ronald Simon, Guido Sauter, Sarah Minner. Improved prediction of prostate cancer prognosis by using a multiparametric molecular classifier. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4353. doi:10.1158/1538-7445.AM2015-4353</jats:p