Polymorphisms of estrogen-metabolizing genes and breast cancer risk: a multigenic study.
BACKGROUND
Endogenous estrogen plays a very important role in the carcinogenesis and progression of breast cancer. The enzymes involved in the biosynthesis and metabolism of estrogen have been proposed to contribute to this effect. To examine this hypothesis, we conducted a case-control study to investigate the relationship between polymorphisms of genes responsible for estrogen biosynthesis (CYP17, cytochrome P450c17a and CYP19, aromatase cytochrome P450) and estrogen sulfation of inactivation (SULT1A1, sulfotransferase1A1) and the risk of breast cancer in Chinese women.


METHODS
This study involved 213 breast cancer patients and 430 matched controls. PCR-based restriction fragment length polymorphism (RFLP) and short tandem repeat polymorphism (STRP) assays were used to detect the mononucleotide transition of CYP17 and SULT1A1 and tandem repeat polymorphism of CYP19. Logistic regression analyses were used to determine OR and 95% CI of each and all three high-risk genotypes, of all three genotypes combined, and of estrogen exposure factors. The relationship between each high-risk genotype and clinicalpathological characteristics were also assessed.


RESULTS
The frequency of A2 allele of CYP17 was 49.8% in cases and 49.1% in controls (P = 0.82). The frequency of His allele of SULT1A1 was significantly higher in cases (13.6%) than in controls (9.5%) (P < 0.05). There was also significant difference of the (TTTA) 10 allele of CYP19 which was 12.4% in cases and 8.2% in controls (P < 0.05). When the CYP17 A2 allele, CYP19 (TTTA) 10 and SULT1A1 His allele were considered as the "putative high-risk" genotype, there was an increased risk of breast cancer with the number of high-risk genotypes in a dose-response effect (trend, P = 0.05). In multivariate analysis, the SULT1A1 genotype remained the most significant determinant for breast cancer, with OR = 2.37 (95% CI 1.23-4.74), followed by CYP19, with OR = 1.75 (95% CI 1.27-3.56). The (TTTA) 10 allele of CYP19 was associated with tumor size, and the His allele of SULT1A1 associated with status of lymph node metastasis.


CONCLUSIONS
This study supports the hypothesis that breast cancer can be initiated by estrogen exposure and that estrogen metabolizing genes are involved in this mechanism. This multigenic model is useful for identifying individuals who are at higher risks of breast cancer.
Han
Ding-Fen
DF
Clinical Laboratory Center Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
Zhou
Xin
X
Hu
Ming-Bai
MB
Xie
Wei
W
Mao
Zong-fu
ZF
Chen
Dong-e
DE
Liu
Fang
F
Zheng
Fang
F
D000328:Adult; D000368:Aged; D001141:Aromatase / Q000235:genetics*; D015239:Arylsulfotransferase / Q000235:genetics*; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*
D004967:Estrogens; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human