Cytochrome P450 17A
CYP17A 34 T>C
The 1000 Genomes Project Database reports a global frequency of 41.1% for the variant C-allele (NIH).
CYP17A Gene Detail
The cytochrome P450, family 17, subfamily A, member 1 (CYP17A1) gene is responsible for the expression of the CYP17 (17α-hydroxylase and 17/20 lyase) enzyme. This is one of the key enzymes involved in the steroidogenic pathway which produces androgens and oestrogens, but also progestins, mineralocorticoids and glucocorticoids.
Mutations in the CYP17A1 gene have been correlated with hormone expression, and thus are said to contribute to the onset of endometriosis, breast, and prostate cancers.
Environmental pollutants, such as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and perfluorinated alkylated acids (PFAAs), are reported as potential endocrine disrupters and has been found positively associated with breast cancer risk. It is recommended that exposure to these should be limited as preventative strategy.
CYP17A 34 T>C
CYP17A1, also known as the 17α-hydroxylase and 17/20 lyase enzyme (P450 17α), is considered essential in the pathway of steroid biosynthesis (especially androgens and oestrogens). The gene is mainly expressed in the adrenal gland, testicular Leydig cells and ovarian theca cells. The enzyme catalyses the conversion of pregnenolone to 17-hydroxy-pregnenolone and the conversion of progesterone to 17-hydroxy-progesterone in the adrenal gland and ovary.
In circulation, estradiol, testosterone and dehydroepiandrosterone (DHEA) are transported through binding to the sex hormone-binding globulin (SHBG) and albumin that affect the bioavailable fraction of the hormones.
The CYP17A1 gene is located on chromosome 10q24-q25 and has eight exons. The 34 T>C polymorphism (T34C) occurs in the 5’UTR, which reportedly affects the gene promoter and subsequent gene expression. The presence of this polymorphism (C-allele, or A2 allele) may lead to the increased synthesis of oestrogens and androgens by creating an additional Sp-1 transcription binding site which increases the activity of the promoter and enhances gene expression.
The development of breast cancer is considered a complex interaction of genes, environment, and lifestyle. Evidence has shown that the lifetime exposure to oestrogen, endogenous or exogenous, is an important pathogenic factor to increase the risk of breast cancer. Oestrogen is mainly produced in the ovaries and mammary glands among premenopausal women, whereas in postmenopausal individuals, adipose tissue is essential for oestrogen biosynthesis. The CYP17 enzyme catalyses the formation of the precursor dehydroepiandrosterone (DHEA), after which it could further be converted into oestrogen through a succession of tissue-specific pathways.
Previous studies have demonstrated that CYP17 could increase the breast neoplasm risk. It is suggested that since the SNP could lead to an enhanced CYP17 transcription rate and increase the CYP17 enzyme level, this could result in an increasing number of bioavailable oestrogens which is likely to affect the risk and aggressiveness of breast cancer.
A recent meta-analysis from Sun et al. (2018) considered 49 studies involving 27 104 cases and 34 218 control subjects to determine the association of the SNP in breast cancer susceptibility. A statistically significant association was only detected amongst postmenopausal women with the heterozygous (TC) genotype. No significant association was found in the overall analysis, neither when a stratified analysis was done according to ethnicity and source.
Several studies in different populations have provided conflicting results. Dunning et al. (1998) demonstrated an association between increased A2 genotype (C-allele) and premenopausal breast cancer, while Feigelson et al. (2001) reported increasing frequency of the C-allele associated with postmenopausal breast cancer in Caucasian women. A positive association has also been observed in Russian and Canadian women, whilst this was not found in several Chinese populations.
Like the findings of Sangrajrang et al. (2009) in Thai women, Farzaneh et al. (2016) have failed to show an association between the 34 T>C polymorphism and breast cancer susceptibility in a case-control study of 270 Iranian women. Meta-analyses evaluating the effect of this SNP in non-Inuit populations also found no associations with breast cancer risk.
In contrast, Yang et al. (2018) reported a negative association between the 34 T>C polymorphism and breast cancer risk in a case-control study of 1143 Chinese Han women. These results suggested that the variant C-allele may provide a protective effect on breast cancer risk in both pre- and postmenopausal women. The authors speculated that the contradicting results from other Chinese populations (where no associations were found) may be attributed to the geographical and lifestyle differences in different regions of the People’s Republic of China, which may have led to differences in the frequencies of genetic variations.
Wielsøe et al. (2018) also reported that Greenlandic Inuit women carrying the C-allele had a reduced breast cancer risk when compared to TT homozygotes. This in line with their previously published study among a Greenlandic Inuit population.
There are inconsistent reports about the role of the 34 T>C polymorphism in the susceptibility to developing polycystic ovary syndrome (PCOS). PCOS is considered a complex, multifactorial and chronic disorder of endocrine glands characterised by hyperandrogenism (hirsutism, acne, alopecia and menstrual irregularity), infertility and metabolic dysfunction (such as hyperinsulinism). This condition is said to affect up to 10% of the women at the age of fertility. Although the major cause of this syndrome is not known, studies have shown that genetic factors play a key role in susceptibility to the disease.
The increased activity of the CYP17A1 enzyme is thought to result in the increased synthesis and secretion of androgens from the ovaries in PCOS. It has been proposed that this SNP may be a useful marker in determining genetic susceptibility to the pathogenesis of PCOS.
A small case-control study in a population from Western Iran with Kurdish ethnic background (50 cases and 109 controls) revealed that the CYP17 TC genotype associated with 2.31-fold increased risk of PCOS. The authors speculated that the increased risk of PCOS in the TC genotype could be attributed to higher promoter activity than is present in the TT genotype. A study carried out by Pusalkar et al. (2009) found a high frequency of the C-allele in PCOS patients compared to controls. Like the report of Pusalkar et al. (2009), the current study indicated that the frequency of the C-allele was significantly increased in women with PCOS compared to the controls and thus suggests that the T34C polymorphism enhanced the risk of PCOS. It has been indicated that the CC genotype has a significant role in hyperandrogenism in PCOS women.
Comparable to the above findings, a previous study in a North Indian population (500 participants) also confirmed a significant association in which a high frequency of the CC genotype was observed in PCOS cases as compared to controls. A study from Diamanti-Kandarakis et al. (2006) also reported a high association of the 34 T>C polymorphism with PCOS in a Greek population.
In contrast to this however, studies conducted in Chinese and Thai populations found that the frequency of genotypes of the 34 T>C polymorphism was not significantly different between women with PCOS and healthy controls. A meta-analysis by Li et al. also demonstrated the absence of an association between the 34 T>C variants and increased risk of PCOS among Caucasian and Asian populations (Rahimi et al. 2019). Rahimi et al. (2019) explained that the controversial reports might be due to various frequencies of the polymorphism among different populations and because of sample size.
Endometriosis is considered an oestrogen-dependent disease and enzymes which regulate the synthesis and metabolism of oestrogen might participate in endometriosis onset. CYP17 is one of the key enzymes involved in oestrogen production, with the CYP17 expression level reportedly upregulated in patients with endometriosis when compared to controls.
Endometriosis is induced by endometrial tissue – it normally grows within the endometrium but can also be deposited and grow outside of it. It is not considered a malignant disease, but it has similar biological behaviours to malignant tumours in terms of invasion, metastasis, and recurrence. Although its pathogenesis remains uncertain, endometriosis has been described as a complex process caused by various factors including hormone and cytokine activity, immune inflammation reaction and genetic influence. Commonly, pelvic pain and infertility are the main symptoms of endometriosis.
A case-control study by Cong et al. (2018), analysing the effects of the CYP17A1 SNP on the susceptibility of endometriosis in 143 cases versus 148 controls, reported a significant association with endometriosis susceptibility but not with endometriosis stages and characteristics. It was concluded that the T-allele may act as a risk factor for endometriosis; the TT and TC genotypes suggested 1.952- and 1.413-fold increased risks respectively. The association remained significant even after adjustment for confounding factors.
Although the abovementioned results are in line with several previous studies, there are also some studies that have reported no significant association between the rs743572 SNP and endometriosis risk. These differences are again thought to be caused by different populations, relatively small sample sizes or other factors.
Androgens play an essential role in the development and function of the prostate and reportedly also in the pathogenesis and progression of prostate cancer. Moreover, experimental and epidemiological data have suggested that also oestrogen signalling may contribute to prostate cancer development and progression.
The presence of the CYP17A1 SNP has been associated with altered levels of circulating DHEA-S (dehydroepiandrosterone sulphate) in Caucasians. It has been reported that the T allele might induce the upregulation of CYP17 in patients with prostate cancer.
A retrospective study from Robles-Fernandez et al. (2017) have found the rs743572 SNP significantly associated with a more progressive prostate cancer in Caucasian men.
A recent meta-analysis carried out by Wang et al. (2015) did not find any significant association between rs743572 and prostate cancer risk, but it was suggested that it might modify the risk of prostate cancer in individuals of African origin. This supports results from an earlier meta-analysis in which Taioli et al. (2013) investigated the association of rs743572 and prostate cancer in 1 580 men from the USA, Caribbean and African descent. Although the pooled results did not yield any significance, the sub-group analysis revealed a 60% increased risk of prostate cancer in African American men carrying the C-allele (TC+CC genotypes).
Interactions between SNPs in the CYP enzymes and several exposures were studied in relation to breast cancer risk, including exposures such as HRT, ingestion of grilled/smoked meat and exposure to persistent organic pollutants (POPs).
Persistent Organic Pollutants
A significant effect modification has been observed in the Wielsoe et al. (2018) study of Greenlandic Inuit women. For the 34T>C polymorphism, the effect of POP exposure, namely polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and perfluoroalkyl acids (PFAAs) on breast cancer risk tended to be stronger for the homozygous T allele carriers than for the variant TC + CC genotypes. It was thus concluded that significant positive associations between POP exposure and breast cancer risk in the TT genotype may exist. The Inuit women carrying the common CYP17A1 T allele also had a higher risk of breast cancer in accordance with the higher PFAA susceptibility seen in TT carriers compared to carriers of the C-allele.
Association between CYP17 T-34C rs743572 and breast cancer risk
Sun et al, 2018.