Andrea Gsur

A POLYMORPHISM IN THE CYP17 GENE IS ASSOCIATED WITH PROSTATE CANCER RISK

CYP17 encodes the enzyme cytochrome P‐450c17α, which mediates both 17α‐hydroxylase and 17,20‐lyase in the steroid biosynthesis pathway. A polymorphism in the 5` promoter region of the CYP17 gene has been described. Steroid hormones, especially androgens, are believed to play a key role in the etiology of prostate cancer. Therefore, polymorphisms in genes involved in the androgen metabolism may affect the risk of prostate cancer. We conducted a case‐control study of 63 patients with untreated histologically proven prostate cancer and 126 age‐matched control men with benign prostatic hyperplasia (BPH) to determine whether a polymorphism in the CYP17 gene is associated with prostate cancer risk. This polymorphism was investigated by PCR/RFLP using DNA from lymphocytes. The transition (T→C) in the risk allele (A2) creates a new recognition site for the restriction enzyme MspAI, which permits designation of the wildtype (A1) and the risk allele (A2). The prevalence of the A2/A2 genotype was significantly higher (P = 0.03) in the cancer group (23.8%) than in the BPH control group (9.5%). We found an increased risk in men carrying 2 A2 alleles (OR = 2.80, 95%CI = 1.02–77.76). For carrier with at least 1 A2 allele, the OR was 0.90 (95%CI = 0.43–1.89). After stratification by median age (66 years) at time of diagnosis, a marked increased risk was found in carriers of the A2/A2 genotype older than 66 years (OR = 8.93, 95%CI = 1.78–49.19, P = 0.01). Although the sample size is rather small and the controls are BPH patients, our results suggest that the CYP17A2/A2 genotype may be a biomarker for prostate cancer risk, especially for older men. Int. J. Cancer 87:434–437, 2000.

Polymorphisms of glutathione‐S‐transferase genes (GSTP1, GSTM1 and GSTT1) and prostate‐cancer risk

Several polymorphic glutathione‐S‐transferase (GST) enzymes are involved in the metabolism of a number of potential prostate carcinogens and are thought to engage in the transport of steroid hormones. A case‐control study was conducted to determine the association of the GSTP1, GSTM1 and GSTT1 polymorphisms and prostate‐cancer risk. The study population consisted of 166 patients with previously untreated, histologically proven prostate cancer and 166 age‐matched control patients with benign prostatic hyperplasia (BPH), all of them Caucasians. In the GSTP1 gene, 2 polymorphic alleles, GSTP1*B and GSTP1*C, have been described in addition to the wild‐type allele, GSTP1*A. Both polymorphic GSTP1 alleles have an A‐to‐G transition in exon 5, causing an isoleucine‐to‐valine change. The GSTP1*C allele has an additional transition from C to T. For GSTM1 as well as GSTT1, the polymorphic allele is a deletion of the gene. The proportion of individuals homozygous for the GSTP1 variant alleles (GSTP1*B/*B, GSTP1*B/*C and GSTP1*C/*C) was significantly lower in prostate‐cancer patients (4.8%) than in BPH controls (14.5%), and the odds ratio (OR) was 0.24 [95% confidence interval (CI) = 0.09–0.61). The heterozygous genotypes (GSTP1*A/*B and GSTP1*A/*C) were also lower in the cancer group, though this was not significant. On the contrary, no significant effect on prostate‐cancer risk was detectable for either GSTM1 (OR = 0.86, 95% CI = 0.55–1.36) or GSTT1 (OR = 0.78, 95% CI = 0.43–1.42). Of the polymorphic GSTs, GSTP1 is the most interesting candidate as a biomarker for prostate‐cancer risk as we found a 76% reduced risk in men homozygous for the polymorphic GSTP1 alleles compared to those with wild‐type GSTP1.

Genetic polymorphisms and prostate cancer risk

The identification of common genetic polymorphisms that influence susceptibility to PC would allow an early risk assessment with earlier and therefore potentially more effective intervention by chemopreventive means. In this review we focus on published case-control studies and meta-analyses of the following polymorphic genes that may play a role in etiology of the androgen receptor (AR), the prostate-specific antigen (PSA), 5α-reductase type II gene (SRD5A2), cytochrome P450c17α (CYP17), cytochrome P4503A4 (CYP3A4) and a putative hereditary PC susceptibility gene, ELAC2.

MDR1 gene expression and its clinical relevance in primary gastric carcinomas

Background. Drug resistance remains a major problem in gastric carcinomas. To evaluate the mechanisms involved in this resistance, the authors determined the expression of the MDR1 gene, a multidrug resistance gene, in primary gastric carcinomas.

MDR1 Gene Expression in Lymphocytes of Patients with Renal Transplants

The MDR1 gene, a multidrug resistance gene, codes for P-glycoprotein which pumps hydrophobic drugs out of the cells. Since cyclosporins also bind to P-glycoprotein and might be pumped by this transmembrane protein, we determined the expression of the MDR1 gene in the lymphocytes of 32 patients with renal transplants. MDR1 RNA expression of lymphocytes was measured by slot blot analysis and compared to the expression of drug-sensitive KB-3-1 cells and multidrug-resistant KB-8-5 cells. MDR1 RNA expression was detected in the lymphocytes of 9 (28%) patients, whereas no expression was seen in the remaining 23 patients. No association between MDR1 RNA expression and transplant function or hematological parameters was observed. However, none of the 6 patients who had transplants for more than 40 months expressed the MDR1 gene in their lymphocytes. In conclusion, expression of the MDR1 gene does occur in lymphocytes of patients with renal transplants and might reduce the immunosuppressive efficacy of cyclosporins through enhanced efflux of cyclosporins.

MDR1 RNA Expression as a Prognostic Factor in Acute Myeloid Leukemia: An Update

In order to confirm our initial report on the negative impact of MDR1 gene expression on the outcome of de novo acute myeloid leukemia (AML), we present an update of our prospective study with a larger number of patients and a longer duration of follow-up. At diagnosis, MDR1 RNA expression of the leukemic cells was negative in 37% and positive in 63% of the patients (N = 79). The complete remission rate of induction chemotherapy was 76% for MDR1 RNA negative and 54% for MDR1 RNA positive patients (p = 0.05). At a median observation duration of 33 months, the duration of overall survival was 19 months for the MDR1 RNA negative patients but only 8 months for the patients with MDR1 gene expression (p = 0.02). Thus the long-term data also indicate that MDR1 gene expression is an unfavourable prognostic factor in AML.

MDR1 Gene Expression in Chronic Lymphocytic Leukemia

In order to assess the clinical role of the MDR1 gene in chronic lymphocytic leukemia (CLL), we determined its expression in the leukemic cells of 39 patients with CLL and compared this with other clinical and laboratory parameters. MDR1 RNA expression was detected in 29 patients. MDR1 RNA transcripts were independent of age, treatment status of the patients and the clinical stage of CLL, but correlated with the white blood cell count and MDR2 RNA transcripts. Expression of the tumor suppressor gene p53 was found in 30 out of 37 patients and was associated with MDR1 RNA expression (P < 0.001). Immunocytochemistry using the monoclonal antibody C219 was performed in 38 patients, and in 28 cases, more than 5% of the leukemic cells were found to express cell surface P-glycoprotein. P-glycoprotein expression correlated with the expression of MDR1 RNA (P = 0.048).