No association of the 5′ promoter region polymorphism of CYP17 gene with prostate cancer risk

Abstract

4Hemocentro de São José do Rio Preto, Sáo Paulo, Brazil CYP17 gene encodes the enzyme cytochrome p450c17a, which mediates two steps in the steroid biosynthesis pathway. Steroid hormones are believed to play a key role in the etiology of prostate cancer. A polymorphic T?C transition in the 5 0 promoter region of CYP17 creates an additional Sp1-type (CCACC box) promoter site (allele A2). We have evaluated the genotypic and allelic distribution of this polymorphism among 92 prostate cancer patients in order to assess risk by comparison with a population-based series of 200 healthy individuals from Brazil. Our results provide no evidence for an association between prostate cancer risk and CYP17 T/C polymorphism. Prostate Cancer and Prostatic Diseases (2002) 5, 28-31. DOI: 10.1038/sj/pcan/4500550Keywords: CYP17 gene; T/C polymorphism; prostate cancer risk IntroductionProstate cancer is the most common malignancy and the third most common cause of cancer mortality in Brazilian men. 1 Studies of risk factors such as occupation, diet, smoking, alcohol and sexual activity are still inconclusive, however, age, ethnicity and family history clearly affect the risk of prostate cancer. 2 -7 There is evidence to support the hypothesis of hormonal etiology of prostate cancer involving androgen action. 8 -10 Androgen is required for differentiation and growth of the prostate in utero and at puberty. 8 Testosterone, the most abundant circulating androgen is synthesized from cholesterol by a series of enzymatic reactions involving the cytochrome p450c17a. The enzyme has a bifunctional active site: the catalytic center performs the 17a-hydroxylation of pregnenolone and progesterone while the 17,20-lyase activity is responsible for the conversions of 17a-hydroxypregnenolone to dehydroepiandrosterone and 17a-hydroxyprogesterone to androstenedione, precursors of testosterone and estrogen. 11 Testosterone is converted to 5a-dihydrotestosterone (DHT) in the prostate by the enzyme 5a-reductase. DHT binds to AR (androgen receptor gene), and the DHT -AR complex transactivates a number of genes with ARresponsive elements. These events ultimately result in cell division in the prostate. 12 The CYP17 gene codes for cytochrome p450c17a enzyme, is located on chromosome 10, spans 6569 bp, and is divided into eight exons. 13 A polymorphic T?C transition in the 5 0 promoter region of CYP17 creates an additional Sp1-type (CCACC box) promoter site. 14 This base pair change also creates a recognition site for the MspA I restriction enzyme, which allows the identification of the CYP17 A2 allele. Since the number of 5 0 promoter elements correlates with promoter activity, it has been proposed that the A2 allele may lead to an increased rate of transcription, thus increasing the prostate cancer risk. 15 Recent in vitro evidence suggests that the 5 0 Sp1 type site resulting from the T to C substitution does not actually bind transcription factor Sp1, but there is still some functional evidence to indicate that this polymorphism may act as a risk facto...

CYP17 gene polymorphisms and prostate cancer risk: A meta‐analysis based on 38 independent studies

“…Characteristics of studies eligible for the current meta‐analysis are presented in Table I 2, 10–28, 30–46. There are 357 papers relevant to the searching words.…”

“…Three hundred two of 357 papers were excluded (126 duplicated of title; 40 were not in human; 36 were not case–control studies; 33 did not explore PCa; 31 did not explore CYP17 gene polymorphisms; 3 were meta‐analysis; 33 were reviews), leaving 55 studies for full publication review. Of these, 16 studies were excluded (7 studies did not explore cancer risk; 9 studies targeted on familial PCa risk), leaving 39 studies 2, 10–28, 30–47. Four articles examined the association in independent populations and thus each of them was treated as two separate studies 11, 36, 37, 46.…”

“…Additional data for detailed genotype frequencies needed were requested from authors for three studies and not available 18, 26, 35. Finally, a total of 38 independent studies including 34,782 cases and 38,626 controls were used in the current meta‐analysis 2, 10–17, 19–25, 27–34, 36–46.…”

Polymorphism in the Androgen Biosynthesis Gene (CYP17), a Risk for Prostate Cancer: A Meta-Analysis

“…With the subgroup analysis of the various genotype models, ethnicity was a major risk factor for prostate cancer. Several authors have reported the association between CYP17 rs743572 polymorphism and the risk of prostate cancer using African ancestry as a determinant ( Lunn et al, 1999 ; Kittles et al, 2001 ; Stanford et al, 2002 ; Cicek et al, 2004 ; Sarma et al, 2008 ; Beuten et al, 2009 ; Dos Santos et al, 2002 ). This meta-analysis disagrees with a study by Wang et al (2011) , who reported no significant association between CYP17 rs743572 polymorphism and prostate cancer in Caucasians and Asians.…”

The role of CYP17A1 in prostate cancer development: structure, function, mechanism of action, genetic variations and its inhibition

“…Some case-control studies have reported an elevated risk for PCa being related to the A1/A2 or A2/A2 genotype (Lunn et al 1999;Gsur et al 2000;Haiman et al 2001;Kittles et al 2001;Yamada et al 2001;Sobti et al 2008;Souiden et al 2011), whereas other studies indicate an association between PCa and the A1/A1 genotype (Wadelius et al 1999;Habuchi et al 2000). Further studies have reported no difference in the distribution of the various alleles among healthy controls and PCa patients (Chang et al 2001;Latil et al 2001;Standford et al 2002;dos Santos et al 2002;Madigan et al 2003;Hamada et al 2007;Sivonova et al 2012;Cai et al 2012;KarimpurZahmatkesh et al 2013;Ersekerci et al 2015;Han et al 2015;Henríquez-Hernández et al 2015).…”