Evaluation of breast cancer risk in a multigenic model including low penetrance genes involved in xenobiotic and estrogen metabolisms.
Breast cancer has become the most frequent cancer among women in Westernized countries. The majority of breast cancers are due to low penetrance genes, which can act with environmental factors, particularly nutrition. Polymorphisms in gene coding for xenobiotic and estrogen metabolic pathways could increase individual cancer susceptibility and lead to the indication of individuals at higher cancer risk. A population-based, case-control study consisting of 911 breast cancer cases and 1,000 healthy control cases was performed. The association between 11 single nucleotide polymorphisms (SNP) in 7 genes and breast cancer risk was investigated in a multigenic model. The CYP1B1-432 Leu-Val and Val-Val genotypes significantly increased risk [odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.08-1.39; OR = 1.51, 95% CI = 1.17-1.94, respectively] similarly as observed with CYP1B1-453 (Asn-Ser genotype: OR = 1.17, 95% CI = 1.00-1.37; Ser-Ser genotype: OR = 1.38, 95% CI = 1.00-1.89). We showed that catechol-O-methyltransferase (COMT) could modulate the risk conferred by CYP1B1, ESR, GSTP1, and NAT2 acetylation phenotype. Additionally, a higher risk conferred by the variant for COMT was noted only for individuals presenting a high waist-to-hip ratio (COMT Val-Met, OR = 1.60, 95% CI = 1.04-2.44; COMT Met-Met, OR = 1.57, 95% CI = 0.98-2.53), suggesting a relationship with abdominal adiposity. In conclusion, COMT constitutes a crucial element in estrogen metabolism by regulating carcinogen metabolites elimination and, consequently, is a major factor in breast cancer risk.
Delort
Laetitia
L
Centre Jean Perrin, and Centre de Recherche en Nutrition Humaine, 63011 Clermont-Ferrand, France.
Satih
Samir
S
Kwiatkowski
Fabrice
F
Bignon
Yves-Jean
YJ
Bernard-Gallon
Dominique J
DJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D015262:Xenobiotics / Q000378:metabolism*
D004967:Estrogens; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D002394:Catechol O-Methyltransferase; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi