Pharmacogenetics of human androgens and prostatic diseases

Prostate cancer (PCa) and benign prostatic hypertrophy (BPH) are two common and growing public health problems in the Western world. We review here the recent biochemical and pharmacogenetic literature related to these two prostatic disorders. We focus first on constitutional ('germline') single nucleotide polymorphism (SNPs) at the steroid 5 alpha-reductase (SRD5A2) locus, which encodes the human prostatic (or Type II) steroid 5 alpha-reductase enzyme. The investigations reviewed point to several uses of personalised medicine at the SRD5A2 locus. In addition, we report on recent identification of somatic pharmacogenetic alterations at the androgen receptor (AR) locus, which encodes the human androgen receptor, suggesting that this also may be a fruitful field of investigation, with important clinical applications. Pharmacogenomic investigation of constitutional and somatic DNA changes in human genes predisposing to cancer may lead to significant advances in chemoprevention, presymptomatic diagnosis and improved treatment of PCa

The genetics of sports injuries and athletic performance.

PURPOSE: in the last two decades, several evidences have been provided to support the relationship between single nucleotide polymorphisms and the susceptibility to develop injuries participating in sport and performance related to sports activity. We report up-to-date review of the genetics factors involved in tendon injuries and athletic performance. METHODS: we searched PubMed using the terms "sports injuries", "athletic performance" and "genetics" over the period 1990 to the present day. We also included non-English journals. RESULTS: most of the currently established or putative tendinopathy susceptibility loci have been analyzed by candidate gene studies. The genes currently associated with tendon injuries include gene encoding for collagen, matrix metallopeptidase, tenascin and growth factors. Several genes have been related to the physical performance phenotypes affecting endurance capacity and muscle performance. The most studied include ACE and ACTN3 genes. CONCLUSIONS: genetics determines the response of an individual to the surrounding environment. Recently, some of the individual genetic variations contributing to the athletic performance and the onset of musculoskeletal injuries, particularly in tendon and ligament tissues, have been identified. However, the identification of the genetic background related to susceptibility to injuries and physical performance of the athletes is challenging yet and further studies must be performed to establish the specific role of each gene and the potential effect of the interaction of these

Genomic biomarkers androgen pathway and prostate cancer

Prostate cancer is the most frequent male malignancy diagnosed in western countries and the second leading cause of cancer-related deaths. The growth and function of the prostate gland depends on androgens. Owing to the importance of androgens in prostate development, genes involved in androgen biosynthesis and metabolism have been extensively studied. In this review, we address recent progress toward the use of inherited and acquired genetic variants to predict susceptibility and clinical outcomes of prostate cancer patients. Many of these genetic variants involve several genes related to the biosynthesis and metabolism of androgens, such as steroid-5-alpha-reductase, alpha polypeptide 2 (SRD5A2), cytochrome P450 (CYP)19A1, CYP17A1, hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 (HSD3B2) and androgen receptor (AR). With increasing knowledge, it may be possible to distinguish indolent from aggressive prostate tumors by molecular fingerprinting. Furthermore, with the emergence of new investigative tools, such as microarray platforms and comparative genomic hybridization (CGH) array, a variety of new genomic biomarkers will be available in the future to provide accurate prognostic and monitoring solutions for individualized patient care

Association of the G289S single nucleotide polymorphism in the HSD17B3 gene with prostate cancer in Italian men

BACKGROUND. Prostate cancer is a significant public health problem in this country. Substantial data support a plausible role for androgens in the etiology of this disease. The human HSD17B3 gene encodes the testicular (or type III) 17beta-hydroxysteroid dehydrogenase enzyme, which catalyzes testosterone biosynthesis in men. METHODS. We have investigated the G289S (glycine at codon 289 replaced by serine) polymorphism at the HSD17B3 locus as a candidate single nucleotide polymorphism (SNP) for prostate cancer risk in constitutional DNA from 103 Italian prostate cancer patients and 109 Italian disease-free centenarians to assess the role of this SNP in susceptibility to prostate cancer. RESULTS. The G289S polymorphism confers a significant increase in risk for prostate cancer (odds ratio = 2.5; 95% confidence interval, 1.03-6.07) in our study population. CONCLUSION. Our data are consistent with a plausible role of the G289S SNP in prostate cancer susceptibility. Therefore, the HSD17B3 gene may be a plausible candidate gene for prostate cancer ris

Pharmacogenetics of human androgens and prostate cancer--an update

Prostate cancer is the most common non-skin cancer in the US; it is the second leading cause of death from cancer among US men, and the seventh leading cause of death in the US. This review examines the recent biochemical and pharmacogenetic literature related to prostate cancer, specifically that which focused on constitutional ('germline') single nucleotide polymorphisms at 'functional candidate' genes for prostate cancer. The investigations summarized in this review demonstrate the need to study the molecular genetics at these loci to rationally develop personalized medicine. In addition, the identification of somatic pharmacogenetic alterations in one of these loci suggests that this may also be a fruitful field of investigations with important clinical applications. Pharmacogenomic investigations of constitutional and tumor DNA may lead to significant advances in chemoprevention, presymptomatic diagnosis and improved treatment of prostate cancer

GIANT SCROTAL ELEPHANTIASIS: AN IDIOPATHIC CASE

Scrotal elephantiasis is very rare disease in industrialized countries, where it is mainly due to surgery, irradiation or malignancies. It can be defined as idiopathic only when the possible congenital, infectious and compressive causes are excluded. We report a case of massive scrotal lymphoedema in an adult Caucasian patient, in Italy. He presented an extremely voluminous scrotal mass measuring 50 x 47 x 13 cm (weight 18 kg), which extended below his knees, invalidating all his daily activities. The patient was hospitalized in order to undergo to surgical treatment. Although genetic causes were searched and the possible role of infectious agents and compressive factors was evaluated, no etiology was ascertained. Histopathologic examination showed non-specific chronic inflammation, confirming the diagnosis of idiopathic elephantiasis. One year after surgical treatment, the patient is healthy without recurrence signs

PENTALOGY OF CANTRELL WITH COMPLETE ECTOPIA CORDIS IN A FETUS WITH ASPLENIA

Cantrell's Pentalogy (CP) is a rare, mainly sporadic spectrum of congenital midline thoracoabdominal defects including sternal anomalies, ventral diaphragmatic hernia, partial absence of the pericardium, supraumbilical abdominal wall defects and congenital heart malformations. The approximate incidence is 1 in 100000, with a 2:1 male predominance. Case: A 25 year-old pregnant woman was referred to the Prenatal Diagnosis Unit of the University Hospital of Padua for multiple congenital malformations at 21 weeks of gestation. A II level ultrasound scan was performed confirming the presence of multiple anomalies compatible with the diagnosis of Cantrell's Pentalogy (CP) associated with complete ectopia cordis. Fetal authopsy furthermore revealed asplenia, which usually presents as part of the heterotaxia spectrum. To our knowledge an association of CP and complete ectopia cordis with asplenia has never been reported so far

"Double Trouble" or an Amplification of the Triploidy Phenotype?

I.F.0.585 -Triploidy occurs in about 1 to 3% of clinically recognizable pregnancies and is typically associated with growth restriction, craniofacial dysmorphisms and congenital anomalies. We report the case of a female fetus with prenatal diagnosis of complete triploidy, polysplenia, bilateral cleft-palate, horseshoe-kidneys and bilateral club-feet. Whereas bilateral cleft-palate, horseshoe-kidneys and bilateral club feet are known to be part of the triploidy-associated malformation spectrum, polysplenia, which usually occurs as part of the heterotaxia spectrum, has never been associated with triploidy. An amplification of the triploidy phenotype or a "double trouble"