The CAG trinucleotide repeat length in the androgen receptor does not predict the early onset of prostate cancer

Objective To relate the repeat length of the androgen-receptor CAG trinucleotide to the age of onset of prostate cancer, stage and grade of disease. Patients and methods After obtaining ethical approval, 265 patients with locally confined or locally advanced/metastatic prostate cancer were identified and evaluated for age at diagnosis (less than 65 years and greater than 75 years). DNA was extracted from peripheral blood lymphocytes and 1 mug aliquots subjected to polymerase chain reaction using fluorescently labelled primers. Samples were then run on an ABI 377 gene scan analysis gel with an internal molecular weight marker. The length of the CAG repeat was determined by comparing the gene scan product size to samples where the CAG repeat length had been quantified using direct sequencing. The Kruskal-Wallis, Mann-Whitney and Wilcoxon two sample tests were used to analyse the data. Results The mean (range) length of the CAG repeat in the androgen receptor was 22.2 (10-31) in the younger and 22.5 (16-32) in the older group, and was not statistically different. There was no significant association between the CAG repeat length and the age of onset of prostate cancer (P = 0.568) or with stage (P = 0.577) and grade (P = 0.891) of prostate cancer. Conclusion These results suggest that there is no correlation between the androgen receptor CAG repeat length and the age of onset, stage and grade of prostate cancer, confirming recent doubts from other similar studies of a suggested correlation between shorter androgen receptor CAG repeat and early onset and aggressiveness of prostate cancer

The impact of androgen receptor polymorphism and parental ethnicity on semen quality in young men from Latvia

Recent studies on young men from the general population have demonstrated geographic and ethnic differences in semen quality. The aim of this study was to investigate whether reported ethnic differences in semen quality might be associated with the maternally derived CAG and GGN polymorphisms in the androgen receptor gene or paternal ethnicity. In total 114 military conscripts from Latvia were included in the study. Information on maternal and parental ethnicity was collected by questionnaires. CAG and GGN repeats were analysed by direct sequencing of leukocyte DNA. Men with Latvian mothers (n = 83) had marginally shorter CAG repeat length (21.6 ± 2.9) as compared with those with non-Latvian mothers (22.9 ± 3.2, n = 31), not reaching statistical significance (p = 0.053). Sperm concentration did not differ significantly between these two groups (76 ± 59 and 70 ± 52, p = 0.9 respectively). In contrast, significantly higher sperm concentration and total sperm count were found in men with Latvian fathers (n = 77) as compared with men with non-Latvian fathers (n = 37) (80 ± 61 vs. 62 ± 48, p = 0.035, for sperm concentration and 225.7 ± 209 vs. 158.4 ± 134.4, p = 0.002, for total sperm count respectively). CAG repeat length did not correlate with any semen parameters in the whole population. However, GGN repeat length correlated with semen volume: men with GGN > 23 presented with higher semen volume (3.2 ± 2.1) as compared with men with GGN = 23 (2.6 ± 1.3, p = 0.04) or GGN < 23 (2.0 ± 1.2, p = 0.006). We conclude that GGN repeat length has an impact on semen volume, whereas differences in sperm numbers are associated with the paternal ethnicity.Peer reviewe

Copy number and gene expression differences between African American and Caucasian American prostate cancer

<p>Abstract</p> <p>Background</p> <p>The goal of our study was to investigate the molecular underpinnings associated with the relatively aggressive clinical behavior of prostate cancer (PCa) in African American (AA) compared to Caucasian American (CA) patients using a genome-wide approach.</p> <p>Methods</p> <p>AA and CA patients treated with radical prostatectomy (RP) were frequency matched for age at RP, Gleason grade, and tumor stage. Array-CGH (BAC SpectralChip2600) was used to identify genomic regions with significantly different DNA copy number between the groups. Gene expression profiling of the same set of tumors was also evaluated using Affymetrix HG-U133 Plus 2.0 arrays. Concordance between copy number alteration and gene expression was examined. A second aCGH analysis was performed in a larger validation cohort using an oligo-based platform (Agilent 244K).</p> <p>Results</p> <p>BAC-based array identified 27 chromosomal regions with significantly different copy number changes between the AA and CA tumors in the first cohort (Fisher's exact test, P < 0.05). Copy number alterations in these 27 regions were also significantly associated with gene expression changes. aCGH performed in a larger, independent cohort of AA and CA tumors validated 4 of the 27 (15%) most significantly altered regions from the initial analysis (3q26, 5p15-p14, 14q32, and 16p11). Functional annotation of overlapping genes within the 4 validated regions of AA/CA DNA copy number changes revealed significant enrichment of genes related to immune response.</p> <p>Conclusions</p> <p>Our data reveal molecular alterations at the level of gene expression and DNA copy number that are specific to African American and Caucasian prostate cancer and may be related to underlying differences in immune response.</p

Molecular Basis of Prostate Cancer Diagnostics and Therapeutics

Prostate Cancer is now the second biggest cause of cancer mortality in the UK. Media coverage has been rising, with some attributing to a rise in the cases diagnosed and treated in the NHS down to the “Fry and Turnbull effect”. Our understanding of prostate cancer has increased tremendously in the past decades, with advances in molecular biology and genomics driving the way to new treatments and diagnostics. This Special Edition of Translational Andrology and Urology 2019: Prostate Cancer Biology and Genomics aims to review the current state of prostate cancer genomics, proteomics, diagnostics and treatment

Novel urinary and serological markers of prostate cancer using proteomics techniques: an important tool for early cancer diagnosis and treatment monitoring

In Africa, Prostate cancer (PCa) is the most frequently diagnosed solid organ tumour in males and use of prostate specific antigen (PSA) is presently fraught with diagnostic inaccuracies. Not least, in a multi-ethnic society like South Africa, proteome differences between African, Caucasian and Mixed-Ancestry PCa patients are largely unknown. Hence, discovery and validation of affordable, non-invasive and reliable diagnostic biomarkers of PCa would expand the frontiers of PCa management. We have employed two high-throughput proteomics technologies to identify novel urine- and blood-based biomarkers for early diagnosis and treatment monitoring of prostate cancer in a South African cohort as well as elucidate proteome differences in patients from our heterogeneous cohort. We compared the urinary proteomes of PCa, Benign Prostatic Hyperplasia (BPH), disease controls comprising patients with other uropathies (DC) and normal healthy controls (NC) both by pooling and individual discovery shotgun proteomic assessment on a nano-Liquid chromatography (nLC) coupled Hybrid Quadrupole-Orbitrap Mass Spectrometer platform. In-silico verification of identified biomarkers was performed using the Human Protein Atlas (HPA) as well as SRMAtlas; and verified potential biomarkers were experimentally prevalidated using a targeted parallel reaction monitoring (PRM) proteomics approach. Further, we employed the CT100+ antigen microarray platform to assess the differential humoral antibody response of PCa, DC and BPH patients in our cohort to a panel of 123 tumour-associated cancer antigens. Candidate antigen biomarkers were analyzed for ethnic group variation in our cohort and potential cancer diagnostic and immunotherapeutic inferences were drawn. Using these approaches, we identified 5595 and 9991 non-redundant peptides from the pooled and individual experiments respectively. While nine proteins demonstrated ethnic trend, 37 and 73 proteins were differentially expressed by pooled and individual analysis respectively. All 32 verified biomarkers were prevalidated with parallel reaction monitoring. Good PRM signals for 12 top ranking biomarker was observed, including PSA and prostatic acid phosphatase. We also identified 41 potential diagnostic and immunotherapeutic antigen biomarkers. Proteogenomic functional pathway analyses of differentially expressed antigens showed similar enrichments of biologic processes. We identified herein novel urinary and blood-based potential diagnostic biomarkers and immunotherapeutic targets of PCa in a South African PCa Cohort using multiple proteomics approaches

THE INFLUENCE OF IN UTERO MATERNAL AND CHILD FACTORS ON TELOMERE LENGTH AND POSSIBLE DIFFERENCES BY RACE: CLUES TO THE RACIAL DISPARITY IN PROSTATE CANCER

There is a pronounced racial disparity in prostate cancer risk and mortality. Modifiable factors in adulthood that explain the disparity have not been identified. Whether racial differences in utero may account for this disparity is understudied. Shorter telomeres have been associated with cancer, and telomere length (TL) at birth is hypothesized to set the trajectory for lifetime telomere shortening and influence adult disease risk including prostate cancer. TL is heritable but telomeres also shorten with cell replication and oxidative damage, and thus may serve as an indicator of cumulative exposure. We investigated the association of in utero maternal and neonate factors with cord blood TL, and whether TL differences between black and white male neonates, as a marker for inherent and exposure racial differences in utero, may explain some of the prostate cancer disparity. We also addressed whether TL differs by race in adult males. We used the Hormones in Umbilical Cord Blood Study (HUB) and Expanded HUB (EHUB) to evaluate whether TL differs by race in neonates, and to estimate associations between maternal and neonate factors and TL. We used the Health Professionals Follow-up Study (HPFS) to evaluate midlife racial differences and associations. In HUB, no factors were associated with TL, and TL did not differ by race. In EHUB, higher pre-pregnancy maternal BMI and less education were inversely associated with neonate TL. Black mothers and neonates had shorter telomeres compared to whites but adjustment for BMI and education eliminated this difference. Maternal and neonate TL were moderately positively correlated regardless of race and after adjustment for confounders. In HPFS, waist circumference, physical inactivity, and smoking were inversely associated with TL but TL did not differ by race before or after adjusting for these factors. Our hypotheses were not supported in HUB or HPFS but were in EHUB. In EHUB the maternal-neonate TL correlation suggests that TL may differ by race at birth due in part to inherent and, in part, racial differences in maternal factors. These findings inform the prostate cancer racial disparity and the influence of the in utero environment on offspring adult disease risk

Repeticiones polimórficas CAG y GGC del gen receptor de andrógenos como factores de riesgo asociadas al cáncer prostático en determinados grupos poblacionales del Ecuador 2004-2010.

En Ecuador al igual que en otros países, el cáncer de próstata es una de la forma más frecuente de cáncer, constituyendo la segunda causa de muerte por cánceres en la población masculina. Al ser hormono dependiente se relaciona con hormonas esteroides, entre los genes relacionados con el metabolismo de los andrógenos se encuentra el gen receptor de andrógenos (AR), el exón 1 de este gen contiene dos trinucleótidos de repetición polimórfica (CAG y GGC). Para verificar la hipótesis planteada, de que alteraciones en el tamaño de estas repeticiones confieren riesgo, se realizó un estudio de caso-control conformado por alrededor de 256 individuos mestizos ecuatorianos. Determinando mediante técnicas moleculares que repeticiones ≤22 CAG y ≤21 CAG + ≥17GGC se relacionan con un mayor riesgo de cáncer y estadios avanzados...In Ecuador, as in other countries, prostate cancer is one of the most common form of cancer, constituting the second cause of death by cancer in the male population. As relates hormone dependent steroid hormones, among genes related to the metabolism of androgens is the androgen receptor gene (AR), exon 1 of the gene contains two polymorphic trinucleotide repeat (CAG and GGC). To test the hypothesis, that changes in the size of these repeats confer risk, we conducted a case-control study consisting of about 256 Ecuadorian mestizos. Determining molecular techniques CAG repeats ≤ 22 and ≤ 21 CAG + ≥ 17GGC are associated with an increased risk of cancer and advanced stages..

The associations between genetic variants body composition, and blood pressure in Afro-Caribbean men from Tobago

Prostate cancer is one of the most common malignancy affecting blacks worldwide. Blacks have a higher incidence and prevalence of prostate cancer than Caucasians. Treatment for prostate cancer usually involves androgen deprivation therapy. Even though androgen deprivation therapy has a high efficacy there are many deleterious side effects such as increase in body fat. Consequently, we investigated the association between androgen deprivation therapy for prostate cancer and the rate of change of percent total body fat in a cohort of Afro-Tobagonian men. Case-control analysis of 1691 men in our study indicated that, men with prostate cancer exposed to ADT had higher increases in percent total body fat over time compared to unexposed men.Likewise, obesity and hypertension disproportionately affects individuals of African descent. These complex diseases are multifactorial in origin and are typically controlled by many genes. Consequently, we investigated the association between ADRB2, body composition and blood pressure. We also investigated the association between AR CAG repeats and body composition. Cross-sectional analysis of 2,584 men in our cohort indicated that, men with shorter AR CAG repeats had higher body fat measurements (DEXA). We found that the direction of the association was opposite what we had anticipated, of men with longer AR CAG repeats having higher body fat measurements. 1,965 men were investigated cross-sectionally to determine the association between ADRB2, body composition and blood pressure. We found no association between ADRB2, DEXA measures of body fat and blood pressure.In our cohort of Afro-Tobagonian men AR CAG repeats and ADRB2 did not show an association with our outcome of interest. Even though we had non-significant findings, other genes should be evaluated to assess if an association exists with body composition and blood pressure in Tobago population. These studies are of public health relevance or importance because they contribute epidemiologic information to the body of scientific inforamtion available especially regarding Tobago men

The role of AP-1 transcription factor expression in androgen sensitive and androgen independent prostate cancer

Development of androgen independent prostate cancer (AIPC) carries a poor prognosis. The underlying molecular mechanisms are complex and not completely understood. Androgen receptor dependent and independent mechanisms have been postulated. AP-1 is a transcription factor whose components are nuclear proteins encoded by c-Jun and c-Fos proto-oncogenes. The possible role of c-Jun and c-Fos in contributing to the development of androgen independent prostate cancer in-vivo using paired human prostate cancer tissue samples has not been studied before. Study hypothesis- AP-1 transcription factor related proteins are dysregulated in the emergence of androgen independent prostate cancer. Aims of the study- 1. To establish a paired clinical cohort of patients in which prostate cancer tissue is available at diagnosis of prostate cancer and also following the development of androgen independence in order to test the hypothesis by immunohistochemistry. 2. To evaluate the expression of AP-1 related proteins in androgen sensitive and androgen independent prostate cancer, by immunohistochemistry. We demonstrated that both androgen sensitive and androgen independent prostate cancers express c-Jun, c-Fos, phosphorylated c-Jun, PKC, COX-2 and AR proteins. A significant proportion of tumours expressed high levels of AP-1 at relapse (c-Jun 68.6%, 35/51; P-Jun, 47%, 24/51; c-Fos 40%, 20/51). An increase or no change in AP-1 (c-Jun, P-Jun & c-Fos) was observed in >80% of AlPCs. Also an increase or no change in PKC (55%), COX-2(70%) and AR (90%) protein expression in AlPC was observed. Differences in the levels of protein expression were observed as androgen sensitive prostate tumours progressed to androgen independent state. In androgen sensitive prostate tumours, we demonstrated a statistically significant correlation in expression of c-Jun, c-Fos and p-Jun proteins (table 14). In androgen independent prostate tumours c-Jun expression correlated with phosphorylated c-Jun with statistical significance (p=<0.0001). We also demonstrated that, high levels of phosphorylated c-Jun and an increase in Protein Kinase C expression at relapse were associated with a decrease in the duration of survival from relapse (p=0.003). Protein Kinase C expression correlated with COX-2 expression in both androgen sensitive as well as in androgen independent prostate tumours (p=0.014 & 0.002 respectively). Also AR protein expression correlated with phosphorylated c-Jun expression in both ASPC and AlPC (p=0.003 & 0.07 respectively). This confirms that both the proteins are involved in the progression of ASPC to AlPC as demonstrated in cell line studies [110, 204]. The study has demonstrated that AP-1 related proteins are dysregulated with the emergence of androgen independent prostate cancer in a subset of patients thus proving the hypothesis