DNA repair gene panel mutations in young onset prostate cancer cases in the.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 18-18
Author(s):  
Ros A. Eeles ◽  
Daniel Leongamornlert ◽  
Ed Saunders ◽  
Sarah Wakerell ◽  
Ian Whitmore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gleason Score ◽  
Gene Panel ◽  
Western World ◽  
Tumour Suppressor Genes ◽  
Illumina Hiseq ◽  
Clinical Prognosis ◽  
Young Onset ◽  
Adaptive Combination ◽  
Dna Repair Gene

18 Background: Prostate cancer (PrCa) is the most common solid tumour in men in the Western world. There is substantial evidence that PrCa predisposition is due both to common and rare germline variation. Methods: We screened 167 genes from DNA damage response and repair pathways, within a UK based cohort of young onset cases (diagnosed at < 65 years) and controls. Samples were sequenced using a custom Agilent SureSelectXT bait library and Illumina HiSeq technology and processed using a BWA/GATK 2.8 pipeline. Following sample QC, data were analysed from 1,285 PrCa cases and 1,163 controls. Results: We identified 5,086 single nucleotide variants (SNVs) and 175 indels; 233 unique protein truncating variants (PTVs) with MAF < 0.5% in controls were found in 97 genes of the screening panel. The total proportion of PTV carriers in cases was higher than in controls (14.5% vs. 11.6%, P = 0.036; OR = 1.29, 95% CI 1.01-1.64). This enrichment was greater within the previously reported BROCA gene set of 22 tumour suppressor genes (4.5% vs 2.2%, P = 2.5x10-3; OR = 2.07, 95% CI 1.28-3.34). To identify genes which best to distinguish PrCa cases from controls, we applied the adaptive combination of P values algorithm, ADA, for genes with at least 2 carriers of PTVs. This analysis selected 10 genes, (OR = 3.37, 95% CI 2.05-5.66, PADA= 5.99x10-3); men with PTVs in these were about 3.4-fold more likely to have PrCa (5.8% vs. 1.8%). We subsequently compared aggressive cases (Gleason score ≥ 8, n = 204) with non-aggressive cases (Gleason score ≤ 7, n = 1049) and lethal PrCa cases (cause of death PrCa, n = 183) with indolent cases (Gleason score ≤ 6, n = 563) to evaluate genes associated with poor clinical prognosis. Using ADA, 4 genes were selected for aggressive PrCa ( PADA= 0.006) and 2 of these also for lethal PrCa ( PADA= 0.057). Conclusions: These gene sets provide an 11 gene panel which could be used for clinical testing and will help to facilitate the development of a PrCa specific sequencing panel with both predictive and prognostic potential.

scholarly journals DNA repair gene panel mutations in young onset and aggressive vs non aggressive prostate cancer cases in the UK

2017 ◽  
Vol 28 ◽  
pp. v270
Author(s):  
R. Eeles ◽  
E. Saunders ◽  
S. Wakerell ◽  
I. Whitmore ◽  
C. Cieza-Borrella ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Panel ◽  
Repair Gene ◽  
Aggressive Prostate Cancer ◽  
Young Onset ◽  
Dna Repair Gene ◽  
The Uk

Rare DNA repair gene mutations predispose to young onset and lethal prostate cancer in the UK

2018 ◽  
Vol 44 ◽  
pp. S23
Author(s):  
Rosalind Eeles ◽  
Daniel Leongamornlert ◽  
Edward Saunders ◽  
Sarah Wakerell ◽  
Ian Whitmore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Repair Gene ◽  
Young Onset ◽  
Dna Repair Gene ◽  
The Uk ◽  
Lethal Prostate Cancer

scholarly journals Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel

2019 ◽  
Vol 76 (3) ◽  
pp. 329-337 ◽  
Author(s):  
Daniel A. Leongamornlert ◽  
Edward J. Saunders ◽  
Sarah Wakerell ◽  
Ian Whitmore ◽  
Tokhir Dadaev ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Repair Gene ◽  
Young Onset ◽  
Dna Repair Gene ◽  
The Uk

scholarly journals Phospholipase D2 in prostate cancer: protein expression changes with Gleason score

2019 ◽  
Vol 121 (12) ◽  
pp. 1016-1026 ◽  
Author(s):  
Amanda R. Noble ◽  
Karen Hogg ◽  
Rakesh Suman ◽  
Daniel M. Berney ◽  
Sylvain Bourgoin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Cell Viability ◽  
Gleason Score ◽  
Cell Movement ◽  
Western World ◽  
Prostate Cell ◽  
Prostate Epithelial Cells ◽  
Downstream Effects ◽  
Castrate Resistant

Abstract Background Phospholipases D1 and D2 (PLD1/2) are implicated in tumorigenesis through their generation of the signalling lipid phosphatidic acid and its downstream effects. Inhibition of PLD1 blocks prostate cell growth and colony formation. Here a role for PLD2 in prostate cancer (PCa), the major cancer of men in the western world, is examined. Methods PLD2 expression was analysed by immunohistochemistry and western blotting. The effects of PLD2 inhibition on PCa cell viability and cell motility were measured using MTS, colony forming and wound-healing assays. Results PLD2 protein is expressed about equally in luminal and basal prostate epithelial cells. In cells from different Gleason-scored PCa tissue PLD2 protein expression is generally higher than in non-tumorigenic cells and increases in PCa tissue scored Gleason 6–8. PLD2 protein is detected in the cytosol and nucleus and had a punctate appearance. In BPH tissue stromal cells as well as basal and luminal cells express PLD2. PLD2 protein co-expresses with chromogranin A in castrate-resistant PCa tissue. PLD2 inhibition reduces PCa cell viability, colony forming ability and directional cell movement. Conclusions PLD2 expression correlates with increasing Gleason score to GS8. PLD2 inhibition has the potential to reduce PCa progression.

Rare DNA repair gene mutations predispose to young onset and lethal prostate cancer in the UK

2017 ◽  
Vol 43 (11) ◽  
pp. 2221-2222
Author(s):  
Rosalind Eeles ◽  
Daniel Leongamornlert ◽  
Edward Saunders ◽  
Sarah Wakerell ◽  
Ian Whitmore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Repair Gene ◽  
Young Onset ◽  
Dna Repair Gene ◽  
The Uk ◽  
Lethal Prostate Cancer

scholarly journals Prediction of prostate cancer gleason score upgrading from biopsy to radical prostatectomy (RP) using a validated 17-gene panel assay

2018 ◽  
Vol 29 ◽  
pp. viii293
Author(s):  
J. Cullen ◽  
H.J. Lawrence ◽  
Y. Chen ◽  
R. Lu ◽  
S. Srivastava ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Gleason Score ◽  
Gene Panel

scholarly journals Establishing a Urine-Based Biomarker Assay for Prostate Cancer Risk Stratification

2020 ◽  
Vol 8 ◽  
Author(s):  
Jinan Guo ◽  
Dale Liu ◽  
Xuhui Zhang ◽  
Heather Johnson ◽  
Xiaoyan Feng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Stratification ◽  
Gleason Score ◽  
Prospective Cohort ◽  
Lower Risk ◽  
Treatment Decision ◽  
Gene Panel ◽  
Urine Test ◽  
Non Invasive ◽  
Lower Accuracy

One of the major features of prostate cancer (PCa) is its heterogeneity, which often leads to uncertainty in cancer diagnostics and unnecessary biopsies as well as overtreatment of the disease. Novel non-invasive tests using multiple biomarkers that can identify clinically high-risk cancer patients for immediate treatment and monitor patients with low-risk cancer for active surveillance are urgently needed to improve treatment decision and cancer management. In this study, we identified 14 promising biomarkers associated with PCa and tested the performance of these biomarkers on tissue specimens and pre-biopsy urinary sediments. These biomarkers showed differential gene expression in higher- and lower-risk PCa. The 14-Gene Panel urine test (PMP22, GOLM1, LMTK2, EZH2, GSTP1, PCA3, VEGFA, CST3, PTEN, PIP5K1A, CDK1, TMPRSS2, ANXA3, and CCND1) was assessed in two independent prospective and retrospective urine study cohorts and showed high diagnostic accuracy to identify higher-risk PCa patients with the need for treatment and lower-risk patients for surveillance. The AUC was 0.897 (95% CI 0.939–0.855) in the prospective cohort (n = 202), and AUC was 0.899 (95% CI 0.964–0.834) in the retrospective cohort (n = 97). In contrast, serum PSA and Gleason score had much lower accuracy in the same 202 patient cohorts [AUC was 0.821 (95% CI 0.879–0.763) for PSA and 0.860 (95% CI 0.910–0.810) for Gleason score]. In addition, the 14-Gene Panel was more accurate at risk stratification in a subgroup of patients with Gleason scores 6 and 7 in the prospective cohort (n = 132) with AUC of 0.923 (95% CI 0.968–0.878) than PSA [AUC of 0.773 (95% CI 0.852–0.794)] and Gleason score [AUC of 0.776 (95% CI 0.854–0.698)]. Furthermore, the 14-Gene Panel was found to be able to accurately distinguish PCa from benign prostate with AUC of 0.854 (95% CI 0.892–0.816) in a prospective urine study cohort (n = 393), while PSA had lower accuracy with AUC of 0.652 (95% CI 0.706–0.598). Taken together, the 14-Gene Panel urine test represents a promising non-invasive tool for detection of higher-risk PCa to aid treatment decision and lower-risk PCa for active surveillance.

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