Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA.

BACKGROUND: Prostate cancer is a very common disease in more-developed countries, but its cause is largely unknown. It is an androgen-dependent cancer, and androgens have been proposed as having a substantial role in predisposition to the disease. Thus, variations in androgen metabolism genes may affect risk of this disease. METHODS: We screened 216 African-American and 172 Hispanic men with prostate cancer, and 261 African-American and 200 Hispanic healthy men (controls), from a large prospective cohort study (the Hawaii-Los Angeles Multiethnic Cohort Study) for a mis-sense substitution in the human prostatic (or type II) steroid 5alpha-reductase (SRD5A2) gene, the product of which controls metabolic activation of testosterone to dihydrotestosterone. This mis-sense substitution results in an alanine residue at codon 49 being replaced with threonine (A49T). We also reconstructed this mutation in the SRD5A2 cDNA, and overexpressed the enzyme in mammalian tissue culture cells. FINDINGS: The A49T aminoacid substitution in the SRD5A2 gene increased the risk of clinically significant disease 7.2-fold in African-American men (95% CI=2.17-27.91; p=0.001) and 3.6-fold in Hispanic men (1.09-12.27; p=0.04). The mutant enzyme had a higher in-vitro Vmax than the normal enzyme (9.9 vs 1.9 nmol min(-1) mg(-1)). INTERPRETATION: The A49T variant of the SRD5A2 gene may be a significant contributor to the incidence of prostate cancer in African-American and Hispanic men in Los Angeles. We estimate that the population attributable risk due to this aminoacid substitution for clinically significant disease is about 8% in both populations. Increased conversion of testosterone to dihydrotestosterone catalysed by this variant steroid 5alpha-reductase enzyme may be the cause of the increased risk.

Identification of two germline point mutations in the 5'UTR of the androgen receptor gene in men with prostate cancer.

PURPOSE: As part of an ongoing study to identify germline mutations and/or polymorphisms in the androgen receptor (AR) gene which might be associated with prostate cancer, the 5'-untranslated region (5'UTR) of the AR gene was screened in genomic DNA of prostate cancer cases. This region, which is > 1 kb in length, might modulate AR expression by affecting transcription and/or translation rates. A life-time exposure to enhanced AR expression, in turn, could potentially predispose to prostate cancer. MATERIALS AND METHODS: Genomic DNA samples from 38 prostate cancer cases were analyzed for mutations in the 5'UTR of the AR gene. RESULTS: Two mutations were identified. One mutation, G2T, is located within the AR transcription initiation site 1 (AR-TIS I), and the second, C214A, within a GC rich region of the 5'UTR. CONCLUSIONS: Although 5'UTR mutations in the AR gene might only rarely occur in men with prostate cancer, the occasional mutation in this area may contribute to the disease by altering rates of transcription and/or translation of this gene.

Bladder augmentation in the prevention of cyclophosphamide-induced haemorrhagic cystitis in the rat model.

OBJECTIVE: To evaluate the effects of cyclophosphamide on the bowel mucosa of the rat and to determine whether urothelium can be protected from the effects of haemorrhagic cystitis which can occur after treatment with cyclophosphamide. MATERIALS AND METHODS: Thirty Sprague-Dawley rats were divided into three groups, 10 undergoing a control (sham) operation, 10 an ileal bladder augmentation and 10 a colonic bladder augmentation. Each rat underwent the appropriate surgical procedure and after a recovery period of 2 weeks, was injected with cyclophosphamide. Urine specimens were collected 24 h after the injection and analysed for gross and microscopic haematuria. The rats were killed humanely 48 h after injection and the bladders examined for haemorrhage, oedema, attenuation, inflammation and erosion. RESULTS: None of the 20 augmented rats developed gross haematuria and only four developed microscopic haematuria, compared with the control rats where six of 10 developed gross haematuria and nine developed microscopic haematuria. In addition, the control rats had moderate to severe haemorrhage, oedema and attenuation compared with only mild changes in the augmented rats. This protection was significant for both the bowel mucosa and urothelium. CONCLUSIONS: It is possible that the administration of cyclophosphamide in patients with urinary diversion carries little risk of haemorrhagic cystitis. We propose that this protective mechanism is secondary to a substance secreted by the intestinal mucosa that may bind acrolein and render it inactive. Alternatively, this may be secondary to the production of mucus and its ability to coat and protect the epithelium.

Management and evaluation of localized amyloidosis of the bladder: two case reports.

Localized amyloidosis of the bladder is a rare cause of hematuria, which is often confused with bladder cancer. We present case histories of two patients which illustrate the evaluation and management of this entity. The diagnosis is usually made with biopsy and subsequent pathologic examination. Conservative management is attempted initially but must be individualized according to the clinical course of each patient. Transurethral resection will suffice in most instances but occasionally cystectomy is indicated to control local disease.