Variants in estrogen-biosynthesis genes CYP17 and CYP19 and breast cancer risk: a family-based genetic association study

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
Breast cancer research: BCR (Impact Factor: 5.49). 01/2005; 7(1):R71-81. DOI: 10.1186/bcr951
Source: PubMed


Case-control studies have reported inconsistent results concerning breast cancer risk and polymorphisms in genes that control endogenous estrogen biosynthesis. We report findings from the first family-based association study examining associations between female breast cancer risk and polymorphisms in two key estrogen-biosynthesis genes CYP17 (T-->C promoter polymorphism) and CYP19 (TTTA repeat polymorphism).
We conducted the study among 278 nuclear families containing one or more daughters with breast cancer, with a total of 1123 family members (702 with available constitutional DNA and questionnaire data and 421 without them). These nuclear families were selected from breast cancer families participating in the Metropolitan New York Registry, one of the six centers of the National Cancer Institute's Breast Cancer Family Registry. We used likelihood-based statistical methods to examine allelic associations.
We found the CYP19 allele with 11 TTTA repeats to be associated with breast cancer risk in these families. We also found that maternal (but not paternal) carrier status of CYP19 alleles with 11 repeats tended to be associated with breast cancer risk in daughters (independently of the daughters' own genotype), suggesting a possible in utero effect of CYP19. We found no association of a woman's breast cancer risk either with her own or with her mother's CYP17 genotype.
This family-based study indicates that a woman's personal and maternal carrier status of CYP19 11 TTTA repeat allele might be related to increased breast cancer risk. However, because this is the first study to report an association between CYP19 11 TTTA repeat allele and breast cancer, and because multiple comparisons have been made, the associations should be interpreted with caution and need confirmation in future family-based studies.

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    • "These polymorphisms were investigated in postmenopausal women or elderly men. In particular, several studies evidenced an association between the number of TTTA repeats and estrogen levels, breast cancer, or osteoporotic risk [77–83]. More recently other polymorphic variants within the promoter region of the CYP19A1 gene have been widely investigated and associated with BMD in both genders as well as with susceptibility to breast or uterine cancer in females [84–86]. "
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    ABSTRACT: Aromatase is a specific component of the cytochrome P450 enzyme system responsible for the transformation of androgen precursors into estrogens. This enzyme is encoded by the CYP19A1 gene located at chromosome 15q21.2, that is, expressed in ovary and testis, but also in many extraglandular sites such as the placenta, brain, adipose tissue, and bone. The activity of aromatase regulates the concentrations of estrogens with endocrine, paracrine, and autocrine effects on target issues including bone. Importantly, extraglandular aromatization of circulating androgen precursors is the major source of estrogen in men. Clinical and experimental evidences clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, the attainment of peak bone mass, pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity may significantly affect bone loss and fracture risk in men.
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    • "PCR products from two heterozygous subjects were cloned and 10 clones of each subject were sequenced. Previous reports described various classifications for the TTTA n repeats: the number of repeats on each allele was dichotomized into two groups based on the number of repeats such as '7 repeats/more than 7 repeats' (Van Pottelbergh et al., 2003; Tofteng et al., 2004; Paynter et al., 2005; Tsuchiya et al., 2006; Huang et al., 2007, 2008), '8 repeats/more than 8 repeats' (Masi et al, 2001; Salmen et al., 2003; Suzuki et al., 2003), '9 repeats/more than 9 repeats' (Remes et al., 2003; Gennari et al., 2004; Lorentzon et al., 2006; Czajka-Oraniec et al., 2008), '10 repeats/more than 10 repeats' (Miyoshi et al., 2000; Baxter et al., 2001; Okobia et al., 2006), '11 repeats/more than 11 repeats' (Masi et al., 2001; Ahsan et al., 2005) or '12 repeats/ more than 12 repeats' (Kristensen et al., 2000). There was a concordance of results among these studies, in that a higher number of repeats were associated with higher estrogen levels. "
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    • "Variant CC allele of CYP17 is associated with increased enzyme activity and higher life time exposure of estrogens. Women carrying the CC allele were reported to be associated with an increased risk of advanced breast cancer (Feigelson et al., 1997, Bergman-Jungestrom et al., 1999, Huang et al., 1999, Spurdle et al., 2000, Chacko et al., 2004); while other studies failed to show this association (Hamajima et al., 2000; Ambrosone et al., 2003; Mitrunen et al., 2000; Wu et al., 2003; Ahsan et al., 2005; Helzlsouer et al., 1998). The proportion of CC alleles among South Indian women in this study (10.8%) is similar to that of the Caucasian population (8-17%) (Weston et al., 1998; Cui et al., 2003; Hefler et al., 2004). "
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