Influence of genetic polymorphisms in P450 C17[alpha](T27C), catechol-O-methyltransferase (VAL158MET), and activity level of cytochrome P450 1A2 on mammographic density levels and other risk factors for breast cancer.
Published: 2004
Language: eng
Number of pages: 247
Description: The objective of this thesis was to study the genetic basis of ovarian hormone metabolism and its potential influence on mammographic density levels and other risk factors for breast cancer. Using a cross-sectional design, polymorphisms in 2 genes, P450 c17alpha (CYP17 , T27C, A1 and A2 allele, respectively) and catechol-O-methyltransferase ( COMT, VAL158MET, COMT*1 and  COMT*2 allele, respectively), as well as cytochrome P450 1A2 (CYP1A2) activity were examined in their relationships with mammographic density, sex hormones, the growth hormone-insulin growth factor-I (IGF-1) axis, and anthropometric variables.Each low activity COMT*2 allele was associated with lower levels of percent breast density amongst pre- but not postmenopausal subjects. In premenopausal women the low activity COMT*2 allele was also associated with lower serum levels of IGF-1, higher levels of FSH and progesterone, and with a larger waist-to-hip ratio, body mass index (BMI), and subscapular skinfold.Information was obtained on risk factors, diet, and anthropometric measures. Blood levels of sex hormones, lipids, and growth factors were measured; and, CYP17 and COMT genotypes were determined. In vivo CYP1A2 activity was assessed by measuring caffeine metabolites in urine. Serum and urinary malondialdehyde (MDA), and MDA-deoxyguanosine adducts in DNA were measured. Mammograms were determined using a computer-assisted method.CYP17 genotype was not associated with mammographic density levels. In premenopausal women, the A2 allele was associated with higher levels of dehydroepiandrosterone sulfate, and in postmenopausal women, with higher levels of total estradiol and lower levels of follicle stimulating hormone. Among premenopausal subjects, interactions were observed between CYP17 genotype and endogenous insulin levels as well as various dietary variables.These findings indicate that CYP17 and  COMT genotypes, as well as CYP1A2 activity are associated with several risk factors for breast cancer.CYPIA2 activity in post-, but not premenopausal, women was positively associated with breast density levels. In premenopausal women, CYP1A2 activity was associated with serum and urinary MDA levels, age, BMI, smoking status, and levels of sex hormone binding globulin (SHBG), total cholesterol, insulin, triglyceride, and caffeine intake. In postmenopausal subjects, independent associations were observed with smoking status, age at menarche, blood triglycerides, SHBG, and IGF-1 levels.
Notes: Adviser: Norman F. Boyd.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2372.