Elsevier

European Journal of Cancer

Volume 36, Issue 18, December 2000, Pages 2375-2379
European Journal of Cancer

Genetic polymorphism in CYP17 and breast cancer risk in Japanese women

https://doi.org/10.1016/S0959-8049(00)00334-8Get rights and content

Abstract

A case–control study was conducted to investigate the association of two genetic polymorphisms (1931T/C and 1951G/A) in the promoter region of the CYP17 gene with breast cancer risk in Japanese women. No significant association was observed between CYP17 polymorphism1951G/A and breast cancer risk (odds ratio (OR)=1.71, 95% confidence interval (CI): 0.28–1.84). In contrast, a significant increase in breast cancer risk (OR=1.82, 95% CI: 1.07–3.12) was observed in CYP171931C/C homozygotes compared with CYP171931T/C heterozygotes and CYP171931T/T homozygotes when women aged ⩾55 years were considered, but such a significant increase was not observed when women aged ⩽54 years were considered (OR=0.96, 95% CI: 0.56–1.63). These results suggest that CYP17 polymorphism1931T/C would be useful in the selection of Japanese women at a high risk for developing breast cancer at the age of ⩾55 years.

Introduction

Epidemiological studies have shown that a longer exposure to a higher level of endogenous or exogenous oestrogens is associated with a high risk of breast cancer. For instance, early menarche, late menopause, obesity and postmenopausal hormone use are well-established risk factors of breast cancers 1, 2. The recent development of molecular biology techniques has enabled us to study the association between breast cancer risk and the genetic polymorphism of the various enzymes involved in oestrogen biosynthesis and metabolism [3]. It is speculated that genetic polymorphism may affect the enzyme activity, and, consequently, the breast cancer risk.

The CYP17 gene encodes the cytochrome P450C17α which is one of the key enzymes involved in oestrogen biosynthesis and mediates both steroid 17α-hydroxylase and 17,20-lyase activity [4]. A genetic polymorphism (T to C transition at 1931) in the promoter region of the CYP17 gene has been reported to be associated with an increased risk of breast cancer in a subgroup of advanced cancer patients [5] or young patients [6]. Since this polymorphism creates a consensus sequence for a SP1 promoter, it is speculated that transcription of the CYP17 gene is enhanced in carriers of the variant allele1931C (A2), resulting in the increased biosynthesis of oestrogen and, consequently, in an increased risk of breast cancer [7]. This speculation is supported by the observations that age at menarche is significantly younger and serum oestrogen levels are significantly higher in carriers of the variant allele1931C than non-carriers [8]. However, other studies have failed to confirm a significant association of CYP17 polymorphism1931T/C with breast cancer risk 9, 10, 11, 12, even in an analysis which involved a large sample size [9]. Thus, the role of this variant allele for breast cancer susceptibility remains to be established.

The studies on CYP17 polymorphism1931T/C have been mainly carried out in Caucasian women and never in Japanese women. Since breast cancer incidence in Japanese women is very low compared with Caucasian women and clinicopathological features of breast cancers are also different, it is conceivable that the risk factors of breast cancer might differ between Japanese and Caucasian women. In addition, a preliminary study has shown that allele frequencies of the CYP19 gene are different among Caucasian and Japanese women 13, 14, 15. Therefore, in the present study, we have investigated the association of the CYP17 polymorphism1931T/C and the CYP17 polymorphism1951G/A with breast cancer risk in Japanese women in a case–control study.

Section snippets

Cases and controls

Eligible cases (n=239) were women who underwent mastectomy or breast conserving surgery in our hospital (Osaka university hospital) during the period of February 1998 to July 1999. They were consecutively recruited in this study. Histological diagnosis of breast cancer (ductal carcinoma in situ (DCIS) (n=10), invasive ductal cancer (n=220), invasive lobular carcinoma (n=6), and other type of carcinoma (n=3)) was confirmed in each case. Healthy females aged between 26 to 62 years without a past

Results

Initially, we have screened the promoter region of the CYP17 gene using the PCR-SSCP method to detect genetic polymorphisms. Sequencing analyses of the aberrant bands revealed two polymorphisms; one is a well-documented T to C transition at 1931, which creates a recognition site for MspA1-I, and the other is a novel G to A transition at 1951, which destroys a recognition site for NaeI (Fig. 1).

The association between the CYP17 MspA1-I polymorphism and breast cancer risk is shown in Table 1.

Discussion

In the present study, we have shown that CYP17 MspA1-I polymorphism is not significantly associated with breast cancer risk when all patients were considered but, after a subset analysis according to the age, we have been able to show that the CYP17 MspA1-I polymorphism is significantly associated with breast cancer risk, i.e. homozygotes of the variant allele1931C are at an increased risk for developing breast cancer at the age of ⩾55 years compared with women with other genotypes. It is

Acknowledgments

This work was supported in part by a Grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan. We thank Dr Takashi Fukutomi, Department of Surgery, National Cancer Hospital, Tokyo, Japan; Dr Zentarou Yamagata, Department of Public Health, Yamanashi Medical University, Yamanashi, Japan; and Dr Kazuo Tamura, Department of Familial Cancer Institute for Advanced Medical Science, Hyogo College of Medicine, Hyogo, Japan for kindly providing control DNA

References (20)

  • Y Abul-Hajj et al.

    Metabolism of pregnenolone by human breast cancer, evidence for 17α-hydroxylase and 17,20-lyase

    Steroids

    (1979)
  • C.C Hsieh et al.

    Age at menarche, age at menopause, height and obesity as risk factors for breast cancerassociations and interactions in an international case–control study

    Int. J. Cancer

    (1990)
  • J.L Kelsey

    Breast cancer epidemiologysummary and future directions

    Epidemiol. Rev.

    (1993)
  • A.M Dunning et al.

    A systematic review of genetic polymorphisms and breast cancer risk

    Cancer Epidemiol. Biomarkers Prev.

    (1999)
  • M.X Zuber et al.

    Expression of bovine 17 alpha-hydroxylase cytochrome P-450 cDNA in nonsteroidogenic (COS 1) cells

    Science

    (1986)
  • H.S Feigelson et al.

    A polymorphism in the CYP17 gene increases the risk of breast cancer

    Cancer Res.

    (1997)
  • M Bergman-Jungestrom et al.

    Association between CYP17 gene polymorphism and risk of breast cancer in young women

    Int. J. Cancer

    (1999)
  • A.H Carey et al.

    Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17

    Hum. Mol. Genet.

    (1994)
  • H.S Feigelson et al.

    Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations

    Cancer Res.

    (1998)
  • A.M Dunning et al.

    No association between a polymorphism in the steroid metabolism gene CYP17 and risk of breast cancer

    Br. J. Cancer

    (1998)
There are more references available in the full text version of this article.

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