Cytochrome P450c17alpha Gene Research Articles

The CYP17A1 −34T > C polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers

Exposure to estrogen has a major effect on breast cancer risk. A polymorphism (-34 T>C; rs743572) in the cytochrome P450c17alpha gene (CYP17A1) encoding an enzyme which controls estrogen levels was reportedly associated with breast cancer risk in average risk populations. The effect of this polymorphism on breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has not been thoroughly investigated. With this aim, 2,221 BRCA1 and BRCA2 mutation carriers (1,313 with breast cancer, 279 with ovarian cancer, and 695 asymptomatic carriers), with either BRCA1 (n=1693) or BRCA2 (n=528) germline mutations from seven centers were genotyped for the -34 T>C CYP17 polymorphism. Genotyping was accomplished using Taqman allelic discrimination, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) or PCR-based restriction-fragment length polymorphism analysis, and limited sequencing. Data were analyzed using Cox proportional hazards models. The hazard ratios (HRs) for breast cancer was 1.02 (95% CI 0.89-1.17, p=0.74) and 1.10 (95% CI 0.72-1.67, p=0.66) for BRCA1 and BRCA2 mutation carriers, respectively. The HRs for ovarian cancer were 1.17 (0.94-1.46, p=0.17) and 0.91 (0.31-2.67, p=0.86) for BRCA1 and BRCA2 mutation carriers, respectively. Results remained unaltered when the Israeli cohort (primarily Ashkenazim) was evaluated separately. In conclusion, there was no overall evidence for an association of the -34 T>C CYP17 polymorphism with either breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

CYP17 5'-UTR MspA1 polymorphism and the risk of premenopausal breast cancer in a German population-based case–control study

IntroductionStudies on the association between the cytochrome P450c17α gene (CYP17) 5'-untranslated region MspA1 genetic polymorphism and breast cancer risk have yielded inconsistent results. Higher levels of estrogen have been reported among young nulliparous women with the A2 allele. Therefore we assessed the impact of CYP17 genotypes on the risk of premenopausal breast cancer, with emphasis on parity.MethodsWe used data from a population-based case–control study of women aged below 51 years conducted from 1992 to 1995 in Germany. Analyses were restricted to clearly premenopausal women with complete information on CYP17 and encompassed 527 case subjects and 904 controls, 99.5% of whom were of European descent. The MspA1 polymorphism was analyzed using PCR-RFLP (PCR–restriction fragment length polymorphism) assay.ResultsThe frequencies of the variant allele among the cases and controls were 43% and 41%, respectively. Overall, CYP17 A1/A2 and A2/A2 genotypes compared with the A1/A1 genotype were not associated with breast cancer, with adjusted odds ratios (ORs) of 1.04 and 1.23, respectively. Among nulliparous women, however, breast cancer risk was elevated for the A1/A2 (OR = 1.31; 95% confidence interval (CI) 0.74 to 2.32) and the A2/A2 genotype (OR = 2.12; 95% CI 1.04 to 4.32) compared with the A1/A1 genotype, with a trend towards increasing risk associated with number of A2 alleles (P = 0.04). Otherwise, the CYP17 polymorphism was found neither to be an effect modifier of breast cancer risks nor to be associated with stage of disease.ConclusionOur results do not indicate a major influence of CYP17 MspA1 polymorphism on the risk of premenopausal breast cancer, but suggest that it may have an impact on breast cancer risk among nulliparous women. The finding, however, needs to be confirmed in further studies.

Estrogen receptor α dinucleotide repeat and cytochrome P450c17α gene polymorphisms are associated with susceptibility to endometriosis

To investigate the association of endometriosis with estrogen receptor alpha (ER alpha) and cytochrome P450c17alpha (CYP17) gene polymorphisms in light of the fact that estrogen plays a role in the pathogenesis of endometriosis and the CYP17 enzyme is involved with estrogen biosynthesis. Prospective study. Genetics and gynecology units. All patients were divided into two groups: group 1, women with endometriosis (n = 119); group 2, normal controls (n = 108). A dinucleotide (thymine-adenine [TA]) repeat polymorphism lying upstream of the ER alpha gene and A1/A2 polymorphism of the CYP17 gene were amplified by polymerase chain reaction, enzyme restriction, and electrophoresis. The ER genotypes were classified into A through T (TA repeats, 10-29). The CYP17 genotypes included indigestible (A1 homozygote), heterozygote, and digestible (A2 homozygote). We compared these polymorphism distributions in both groups. The percentage of genotypes D-G (TA, 13-16) in both groups were 10.5%, 29.4%, 13.0%, and 11.3% in group 1 and 7.9%, 16.7%, 19.9%, and 17.6% in group 2. The genotype E (14 TA repeats) is associated with a higher risk of endometriosis. Proportions of A1 homozygote/heterozygote/A2 homozygote for CYP17 were 26.1%/46.2%/27.7% for group 1 and 14.8%/44.5%/40.7% for group 2, respectively. The A1 homozygote and allele were associated with a higher susceptibility of endometriosis. ER alpha* 14 TA repeats and the CYP17* A1 allele are associated with an increased risk of endometriosis. Both polymorphisms are useful markers for predicting endometriosis susceptibility.

No association of estrogen receptor α and cytochrome P450c17α polymorphisms with age at menopause in a Dutch cohort

Age at menopause is under strong genetic control. So far, genetic variations of only one gene, the PvuII polymorphism of the estrogen receptor alpha (ERalpha) gene, have been shown to be associated with age at onset of menopause. This study aims to investigate whether PvuII, XbaI and B-variant polymorphisms of the ERalpha gene, and the MspAI polymorphism of the cytochrome P450c17alpha (CYP17) gene are associated with age at menopause in a Dutch cohort. DNA was isolated from urine samples of 385 Caucasian women with natural menopause and the genotypes of the four polymorphisms were determined. A questionnaire was used for background characteristics. The genotypes of PvuII, XbaI, MspAI were obtained by PCR restriction fragment length polymorphism analysis. The B-variant was determined with an allele-specific oligonucleotide hybridization method. Two-sided t-tests were performed to assess the association between the four polymorphisms and menopausal age. The PvuII and XbaI polymorphisms were analysed separately as well as in a combined score. The results show that none of the polymorphisms independently, nor the combined genotypes for PvuII and XbaI, were associated with age at natural menopause. No evidence was found for a relationship between common variants of the ERalpha gene and the CYP17 gene with age at natural menopause.

CYP17 gene polymorphisms: prevalence and associations with hormone levels and related factors. a HuGE review.

The cytochrome P-450c17alpha (CYP17 ) gene, located on chromosome 10q24.3, encodes the enzyme cytochrome P-450c17alpha, which functions at key branch points in steroid hormone biosynthesis. Three polymorphisms have been described, but only the single base-pair change in the 5'-untranslated region (5'-UTR) has been investigated to any great extent. In single studies, the variant was associated with reduced messenger RNA level in ovarian cells but not with messenger RNA level in breast tissue. Homozygosity for the 5'-UTR variant is most common in East Asian (32%) and Japanese (22%) populations and is less common among White (mainly European and North American (14%)) and Black (mainly African-American (13%)) populations, but selection biases are likely to have affected these frequency estimates. Genotype appears to influence circulating estrogen levels in premenopausal women, while studies of relations with hormone levels in men have produced inconclusive results. However, relatively few studies have been conducted. Seven of 11 retrospective studies suggested a modest association between genotype and age at menarche. Random error in recall of age at menarche is likely to have attenuated this relation. Associations between genotype and postmenopausal estrogen use and bone mass have been observed in single studies. Further investigation of relations between genotype and hormone levels, exogenous hormone use, and markers of hormonal status may advance understanding of hormonally mediated diseases.

Cytochrome P450c17alpha (CYP17) gene polymorphism is not associated with leiomyoma susceptibility

Estrogen plays a role in the pathogenesis of leiomyoma. The CYP17 gene codes for the cytochrome P450c17alpha enzyme, which is involved in the biosynthesis of estrogen. Our aim was to investigate if CYP17 polymorphism could be a useful marker to predict the susceptibility to leiomyoma. Our sample of female subjects was divided into two groups: (1) with leiomyoma (n = 159); (2) without leiomyoma (n = 128). A 169-bp fragment encompassing the A1/A2 polymorphic site of the CYP17 gene was amplified by polymerase chain reaction (PCR), restricted by enzyme MspA1I and electrophored on agarose gel. Genotypes and allelic frequencies for this polymorphism in both groups were compared. There was no significant difference between the two groups regarding the distribution of the CYP17 gene polymorphism frequencies. The A1 homozygote/heterozygote/A2 homozygote proportions for CYP17 in both groups were: (1) 17.0/46.5/36.5%, and (2) 17.2/45.3/37.5%. The proportions for alleles A1 and A2 were also comparable in the two groups. A1 and A2 allele frequencies were: 7% (40.3/59) in group 1, and 2% (39.8/60) in group 2. No significant association was observed between the risk of leiomyoma and polymorphisms of the CYP 17 gene. So, CYP17 gene polymorphism does not appear to be a useful marker for the prediction of leiomyoma susceptibility.