MP24-10 THE ROLE OF MPMRI IN STRATIFYING PATIENTS WITH INCREASED RISK OF PROSTATE CANCER

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer.CHEK2plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, ofCHEK2on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussedCHEK2∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18) for unselected cases and 3.39 (1.78–6.47) for familial cases, indicating thatCHEK2∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer.

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The modern role of androgen deprivation therapy in the management of localised and locally advanced prostate cancer

Journal of Clinical Urology ◽

10.1177/2051415816654048 ◽

2016 ◽

Vol 9 (2_suppl) ◽

pp. 24-29 ◽

Cited By ~ 6

Author(s):

Charlotte Gunner ◽

Aziz Gulamhusein ◽

Derek J Rosario

Keyword(s):

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Advanced Prostate Cancer ◽

Locally Advanced ◽

Androgen Deprivation ◽

Locally Advanced Prostate Cancer ◽

Curative Intent ◽

Cardiovascular Morbidity And Mortality ◽

Increased Risk

Introduction: Approximately 50% of men diagnosed with prostate cancer will be exposed to androgen deprivation therapy (ADT) at some stage. The role of ADT in the management of metastatic disease has long been recognised, and its place in the management of localised and locally advanced disease has become clearer in the past few years. Nevertheless, concerns remain that some men might not benefit from ADT in earlier-stage disease. The purpose of the current article is to provide a brief narrative review of the role of ADT as part of a strategy of treatment with curative intent, concentrating mainly on key recent developments in the area. Methods: Narrative literature review of key publications in the English language relating to ADT in the management of localised and locally advanced prostate cancer. Results: In locally advanced and high-risk localised prostate cancer, the use of ADT in combination with radiotherapy improves disease-specific and overall survival. There is no evidence to support the use of ADT in the treatment of low-risk localised prostate cancer. There appears to be an increased risk of cardiovascular morbidity and mortality associated with luteinizing hormone-releasing hormone agonists, particularly in men with pre-existing cardiovascular disease, but the relevance of this in the adjuvant/neoadjuvant setting is currently unclear. Conclusions: Future studies should focus on identification of men who are at risk from cardiovascular complications associated with ADT and on the comparison of radiotherapy with ADT versus surgery in the management of localised and locally advanced prostate cancer, particularly with regards to men with pre-existing comorbidities.

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Asthma severity as a contributing factor to cancer incidence: A cohort study

PLoS ONE ◽

10.1371/journal.pone.0250430 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0250430

Author(s):

Laila Salameh ◽

Bassam Mahboub ◽

Amar Khamis ◽

Mouza Alsharhan ◽

Syed Hammad Tirmazy ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Incidence ◽

Asthma Severity ◽

Asthmatic Patients ◽

Increased Risk ◽

Different Types ◽

Asthma Patients ◽

Main Factors ◽

Population Source

Background A putative link between asthma and asthma severity with the occurrence of cancer has been suggested but has not been fully investigated. The objective of this study is to assess the incidence of all types of cancer in a cohort of asthmatic patients. Methods and findings A single center cohort retrospective study was conducted to investigate the role of asthma as a potential risk factor for various cancers. Participants were followed for a period of 9 years from 01/01/2010 to 30/12/2018 and cancer incidence and its determinants were collected in asthmatic patients and controls from the same population source but without any respiratory disease. Overall, 2,027 asthma patients and 1,637 controls were followed up for an average of 9 years. The statistical analysis showed that 2% of asthma patients were diagnosed with various cancers, resulting in an incidence rate of cancer of 383.02 per 100,000 persons per year which is significantly higher than the 139.01 per 100,000 persons per year observed in matched controls (p-value < 0.001). The top four cancers reported among asthmatics were breast, colon, lung and prostate cancer. Lung cancer in asthmatics had the longest diagnosis period with a mean of 36.6 years compared to the shortest with prostate cancer with 16.5 years. Conclusions This study shows that asthma patients are at increased risk of different types of cancers with asthma severity and goiter as the main factors that may increase the risk of developing cancers among asthmatic patients.

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Effect of chronic treatment of combined statins and aspirin on the risk of prostate cancer detection.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.185 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 185-185

Author(s):

Cristina Suarez ◽

Rafael Morales ◽

Jose Placer ◽

Isaac Nunez ◽

Jacques Planas ◽

...

Keyword(s):

Prostate Cancer ◽

Multivariate Analysis ◽

Chronic Treatment ◽

Univariate Analysis ◽

Combined Treatment ◽

Adult Men ◽

Cancer Aggressiveness ◽

Increased Risk ◽

The Impact

185 Background: The role of chronic treatment (ChT) with statins and aspirin on prostate cancer (PC) carcinogenesis is controversial. Both drugs are frequently used in adult men who are at risk of PC, and many of them receive both drugs simultaneously. The impact of the combined treatment (CT) with statins and aspirin on PC risk has never been reported. We proposed to explore the influence of ChT with statins and aspirin in the PC risk detection and their aggressiveness. Methods: 2408 men were consecutively biopsied for cause: PSA > 4 ng/mL (64.4%), abnormal DRE (9%) or both (26.6%). ChT with statins and aspirin (>1 year) was controlled. Median age was 68 years (46–86) and median PSA 7.0 ng/mL (0.7-1279). At least 10 cores, plus 1 to 8 additional cores, were obtained. The PC detection rate was 35.2% and the Gleason score was < 7 in 20.8%, 7 in 50.9% and > 7 (HGPC) in 28.3%. Multivariate and univariate analysis were done and OR calculated to analyze the strength of the relationships. Results: 440 men (18.3%) were receiving statins alone (SA), 160 (6.6%) aspirin alone (AA), and 304 (12.6%) both drugs simultaneously. Multivariate analysis showed that CT was the only independent predictor of a reduced risk of PC detection, p=0.025, (OR 0.589, 95%CI 0.370-0-936). PC was detected in 552 of 1502 men (36.7%) not receiving statins or aspirin, 34.5% (152/440) receiving SA, 40% (64/160) receiving AA, and in 26.3% (80/304) receiving statins and aspirin simultaneously. Related to cancer aggressiveness, multivariate analysis showed that combined treatment predicted significantly an increased risk of HGPC, p=0.013, (OR 2.672, 95%CI 1.226-5.825). HGPC was detected in 136 of 552 (24.6%) PCs detected in men not receiving statins or aspirin, in 40 of 152 (26.3%) PCs detected in men receiving SA, in 24 of 64 (37.7%) PCs detected in men receiving AA, and in 40 of 80 (50%) PCs detected in men receiving statins and aspirin simultaneously. Conclusions: This study suggests that ChT with the combination of statins and aspirin reduce significantly the risk of PC detection in men subjected to prostate biopsy for cause. However, this reduction of PC detection is accompanied by a significant increase of PC aggressiveness.

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Profile study: Genetic prostate cancer risk stratification for targeted screening.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.5054 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 5054-5054

Author(s):

Elena Castro ◽

Elizabeth Bancroft ◽

Natalie Taylor ◽

Tokhir Dadaev ◽

Elizabeth Page ◽

...

Keyword(s):

Prostate Cancer ◽

Genetic Model ◽

Genetic Risk Score ◽

Prostate Cancer Risk ◽

Screening Tools ◽

Risk Scores ◽

Severe Side Effect ◽

Cancer Worry ◽

Increased Risk

5054 Background: Prostate cancer (PC) screening is controversial and better approaches are needed, including a better assessment of individualized PC risk. Several studies have identified a number of common single nucleotide polymorphisms (SNPs) that confer a cumulative risk of PC. We have explored the potential role of genetic markers in identifying men who should be selectively targeted for screening in a population with increased risk of PC due to family history (FH) of the disease. Methods: PROFILE has been developed as a pilot study. The primary aim is to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. Secondary aims are to evaluate the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools in this population. From December 2010 men aged 40-69 with FH of PC were invited into the study until 100 men were enrolled. Blood samples were provided for PSA and DNA extraction. The cumulative SNP risk scores for each patient were calculated by summing 59 risk alleles for each locus using the weighted effect as estimated in previous studies (log-additive model). DW-MRI was performed in 50 patients. All participants were asked to undergo a 10 core PB regardless of baseline PSA. Those who declined PB have been excluded from this analysis. Data on side effects and cancer worry were also collected. Results: 35% of invited men entered the study. Median age was 53 yrs (40-69) and median PSA was 1.15. Ninety men accepted to undergo a PB as primary PC screening. Twenty-two tumours were found and 45% of them were clinically significant [Median age 64yrs (47-69), median PSA 5.4 (0.91-9.3)]. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed better in men with PSA<3(AUC 0.63). No severe side effect or adverse psychosocial variables were noted. Conclusions: Our results indicate that PB is acceptable as a means of PC screening in men with FH of PC. Overall, DW-MRI and PSA were more predictive of PC than the genetic risk score. As more SNPs are found, a larger study is warranted to evaluate their role in the PC screening algorithm.

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Germline heterozygous BLM mutations and prostate cancer risk.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.321 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 321-321

Author(s):

Elisa Ledet ◽

Emmanuel S. Antonarakis ◽

Colin Pritchard ◽

William B. Isaacs ◽

A. Oliver Sartor

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Dna Sequencing ◽

Cancer Patients ◽

Genetic Disorder ◽

Prostate Cancer Risk ◽

Dna Helicase ◽

Cancer Center ◽

Increased Risk

321 Background: The BLM gene encodes a RecQ DNA helicase that is involved in homologous recombination. Biallelic BLM inactivation leads to Bloom syndrome, an inherited genetic disorder marked by chromosomal instability and multiple cancer susceptibilities. Conflicting studies have suggested that heterozygous BLM mutation carriers may have an increased risk of various cancers. Here we explored the role of germline pathogenic BLM mutations in prostate cancer. Methods: Prostate cancer patients with heterozygous BLM mutations were assembled from Tulane Cancer Center (TCC), Johns Hopkins Hospital (JHH) and University of Washington (UW). BLM germline mutations were identified either through commercial germline testing (Invitae), the UW-BROCA panel, or whole-exome sequencing. Corresponding tumor tissue was analyzed by DNA sequencing for somatic alterations. Population level control data were obtained from the Genome Aggregation Database (gnomAD). Results: 6 BLM germline carriers were identified among 985 advanced prostate cancer case; 2/295 TCC patients, 2/172 JHH patients, and 2/518 UW patients. Overall, pathogenic BLM mutations were detected in 0.609% (6/985) of prostate cancer cases. All mutations were loss-of-function truncating lesions (splicing or nonsense alterations). No Ashkenazi BLM mutations were observed. The population frequency of pathogenic or likely pathogenic BLM alterations detected in gnomAD was 0.025% (31/124,589). Compared to gnomAD controls, the relative risk of BLM mutations in prostate cancer patients was 24.3 (95% CI 10.2 to 58.2; P < 0.0001). One family had a pathogenic splice variant in BLM that cosegregated with disease in three of three cases with lethal/high risk prostate cancer. Tumor DNA sequencing was possible in 5 of 6 BLM carriers; no case demonstrated LOH or additional somatic BLM mutations. Interestingly, 2/5 cases on tumor sequencing also had bi-allelic BRCA2 inactivation. Conclusions: Germline BLM mutations may play a role in prostate cancer risk. Given the role of BLM in chromosomal stability and evidence of concurrent BRCA2 inactivation in a subset of cases, larger cohorts and functional analyses will be critical for better understanding the role of BLM in prostate cancer.

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Periprostatic venous androgen levels in a subset of patients with prostate cancer: An investigation into a novel role of testosterone in localized prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.341 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 341-341

Author(s):

Lewis Thomas ◽

Mohammad Alyamani ◽

Jianbo Li ◽

Andrei Purysko ◽

Eric A. Klein ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Volume ◽

Venous Blood ◽

Venous Drainage ◽

Increased Risk ◽

Vein Diameter ◽

Clinically Significant ◽

The Relationship ◽

Androgen Levels

341 Background: While androgens drive prostate cancer (PCa), studies of systemic levels in eugonadal patients have not shown a relationship with development or progression of PCa. This study characterizes the relationship between systemic, local venous, and tissue androgen levels to understand the regulation and influence of androgens on localized PCa. Methods: Peripheral & periprostatic venous blood & prostate tissue were collected from patients undergoing radical prostatectomy (RP). Androgen levels (testosterone (T) and dihydrotestosterone (DHT)) were assessed by mass spectrometry. PCa grade and stage, PSA, prostate volume, and periprostatic vein diameter (PPVD) on MRI were recorded. A second cohort of patients undergoing just prostate MRI (non-surgical) was assessed to investigate the relationship between PPVD and disease severity. Results: Samples were collected from 176 patients. Analysis identified a subset of patients with elevated periprostatic T (ppT) relative to systemic T (sT) including 25% with ppT/sT > 2, 14% with ppT/sT > 4, and 7% with ppT/sT > 10. Patients with ppT/sT > 4 had supraphysiologic T levels in the periprostatic venous blood (mean 4223ng/mL). These patients also had higher than predicted levels of tissue T and DHT (tT/sT of 0.48 vs 0.24 (p = 0.004) and tDHT/sT of 7.31 vs 4.72 (p = 0.011)). In the surgical cohort, PPVD was increased in patients with elevated ppT/sT levels (5.8mm vs 3.7mm, p = 0.013). In the biopsy cohort (n = 200), increased PPVD was associated with an increased risk of diagnosis of PCa (4.39mm vs 3.43mm p = 0.006) and clinically significant PCa (4.35mm vs 3.43mm p = 0.01). Conclusions: In a subset of patients with PCa, periprostatic venous T levels were highly elevated compared to peripheral levels. Tissue T and DHT were also increased, and MRI demonstrated increased PPVD. We hypothesize that collateralization of venous drainage from the gonadal vein leads to both high local T and dilated veins. In a biopsy cohort, increased PPVD was associated with an increased risk of diagnosis of any and clinically significant PCa, suggesting that high periprostatic androgen levels may play a role in development of PCa.

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Polymorphisms in Genes Encoding Glutathione Transferase Pi and Glutathione Transferase Omega Influence Prostate Cancer Risk and Prognosis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.620690 ◽

2021 ◽

Vol 8 ◽

Author(s):

Veljko Santric ◽

Dejan Dragicevic ◽

Marija Matic ◽

Milica Djokic ◽

Marija Pljesa-Ercegovac ◽

...

Keyword(s):

Prostate Cancer ◽

Glutathione Transferase ◽

Redox Homeostasis ◽

Prostate Cancer Risk ◽

Gst Polymorphisms ◽

Increased Risk ◽

Genes Encoding ◽

Gst Polymorphism ◽

First Time

Considering the pleiotropic roles of glutathione transferase (GST) omega class members in redox homeostasis, we hypothesized that polymorphisms in GSTO1 and GSTO2 might contribute to prostate cancer (PC) development and progression. Therefore, we performed a comprehensive analysis of GSTO1 and GSTO2 SNPs’ role in susceptibility to PC, as well as whether they might serve as prognostic biomarkers independently or in conjunction with other common GST polymorphisms (GSTM1, GSTT1, and GSTP1). Genotyping was performed in 237 PC cases and 236 age-matched controls by multiplex PCR for deletion of GST polymorphisms and quantitative PCR for SNPs. The results of this study, for the first time, demonstrated that homozygous carriers of both GSTO1*A/A and GSTO2*G/G variant genotypes are at increased risk of PC. This was further confirmed by haplotype analysis, which showed that H2 comprising both GSTO1*A and GSTO2*G variant alleles represented a high-risk combination. However, the prognostic relevance of polymorphisms in GST omega genes was not found in our cohort of PC patients. Analysis of the role of other investigated GST polymorphisms (GSTM1, GSTT1, and GSTP1) in terms of PC prognosis has shown shorter survival in carriers of GSTP1*T/T (rs1138272) genotype than in those carrying at least one referent allele. In addition, the presence of GSTP1*T/T genotype independently predicted a four-fold higher risk of overall mortality among PC patients. This study demonstrated a significant prognostic role of GST polymorphism in PC.

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Differential Mast Cell Phenotypes in Benign versus Cancer Tissues and Prostate Cancer Oncologic Outcomes

10.1101/2020.07.23.216408 ◽

2020 ◽

Author(s):

Heidi Hempel Sullivan ◽

Janielle P. Maynard ◽

Christopher M. Heaphy ◽

Jiayun Lu ◽

Angelo M. De Marzo ◽

...

Keyword(s):

Prostate Cancer ◽

Mast Cell ◽

Mast Cells ◽

Biochemical Recurrence ◽

Oncologic Outcomes ◽

Cancer Tissue ◽

Increased Risk ◽

Minimum Number ◽

One Year

AbstractWe previously reported that high numbers of mast cells in benign (extra-tumoral) regions of the prostate are associated with worse outcomes after radical prostatectomy including biochemical recurrence and the development of metastases. Herein, on a cohort of 384 men, we performed mast cell subtyping and report that higher minimum number of the tryptase-only (MCT) subset of extra-tumoral mast cells is associated with increased risk of biochemical recurrence (comparing highest to lowest tertiles: HR 2.20, 95% CI 1.32-3.65; P-trend 0.004), metastases (HR 3.60, 95% CI 1.77-7.36; P-trend 0.001), and death from prostate cancer (HR 2.96, 95% CI 1.23-7.08; P-trend 0.02). RNAsequencing of benign versus cancer tissue mast cells revealed differential expression of additional site-specific genes. We demonstrate that genes more highly expressed in tumor-infiltrating mast cells, such as CXCR4 and TFE3, represent an altered tumor microenvironment. C-kit variants were also differentially expressed in benign versus cancer tissue mast cells, with C-kit variant 1 (GNNK+) mast cells identified as more prevalent in extra-tumoral regions of the prostate. Finally, using an established mouse model, we found that mast cells do not infiltrate Hi-Myc tumors, providing a model to specifically examine the role of extra-tumoral mast cells in tumorigenesis. Hi-Myc mice crossed to mast cell knockout (Wsh) mice and aged to one year revealed a higher degree of pre-invasive lesions and invasive cancer in wildtype mice versus heterozygous and knockout mice. This suggests a dosage effect where higher numbers of extra-tumoral mast cells resulted in higher cancer invasion. Overall, our studies provide further evidence for a role of extra-tumoral mast cells in driving adverse prostate cancer outcomes.

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A Systematic Review of Serum γ-Glutamyltransferase as a Prognostic Biomarker in Patients with Genitourinary Cancer

Antioxidants ◽

10.3390/antiox10040549 ◽

2021 ◽

Vol 10 (4) ◽

pp. 549

Author(s):

Kosuke Takemura ◽

Philip G. Board ◽

Fumitaka Koga

Keyword(s):

Prostate Cancer ◽

Systematic Review ◽

Cancer Cells ◽

Elevated Serum ◽

Physiological Role ◽

Epidemiological Studies ◽

Genitourinary Cancer ◽

Increased Risk ◽

Wide Range

γ-Glutamyltransferase (GGT), a membrane-bound enzyme, contributes to the metabolism of glutathione (GSH), which plays a critical physiological role in protecting cells against oxidative stress. GGT has been proposed as a biomarker of carcinogenesis and tumor progression given that GGT activity is important during both the promotion and invasion phases in cancer cells. Moreover, GGT expression is reportedly related to drug-resistance possibly because a wide range of drugs are conjugated with GSH, the availability of which is influenced by GGT activity. While serum GGT activity is commonly used as a quick, inexpensive, yet reliable means of assessing liver function, recent epidemiological studies have shown that it may also be an indicator of an increased risk of prostate cancer development. Moreover, elevated serum GGT is reportedly an adverse prognostic predictor in patients with urologic neoplasms, including renal cell carcinoma, prostate cancer, and urothelial carcinoma, although the background mechanisms have still not been well-characterized. The present review article summarizes the possible role of GGT in cancer cells and focuses on evidence evaluation through a systematic review of the latest literature on the prognostic role of serum GGT in patients with genitourinary cancer.

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