Genetic susceptibility to breast cancer in French-Canadians: role of carcinogen-metabolizing enzymes and gene-environment interactions.
Breast cancer is the most frequent malignancy among women. Since genetic factors such as BRCA1 and BRCA2 as well as reproductive history constitute only 30% of the cause, environmental exposure may play a significant role in the development of breast cancer. Likewise, the relevant enzymes involved in the biotransformation of xenobiotics (from tobacco smoke, diet or other environmental sources) might play a role in breast carcinogenesis. Since individuals with modified ability to metabolize these carcinogens could have a different risk for breast cancer, we investigated the role of cytochromes P-450 (CYP1A1, CYP2D6), glutathione-S-transferases (GSTM1, GSTT1, GSTP1) and N-acetyltransferases (NAT1, NAT2) gene variants in breast carcinogenesis. A case-control study was conducted on 149 women with breast carcinoma and 207 healthy controls, both of French-Canadian origin. The CYP1A1*4 allele was found to be a significant risk determinant of breast carcinoma (OR = 3.3, 95% CI 1.1-9.7), particularly among post-menopausal women (OR = 4.0, 95% CI 1.2-13.8). The frequency of NAT2 rapid acetylators was increased among smokers (OR = 2.6, 95% CI 0.8-8.2), while the NAT1*10 allele conferred a 4-fold increase in risk among women who consumed well-done meat (OR = 4.4, 95% CI 1.0-18.9). These data suggest that CYP1A1*4, NAT1 and NAT2 variants are involved in the susceptibility to breast carcinoma by modifying the impact of exogenous and/or endogenous exposures.
Krajinovic
M
M
Division of Hemato-Oncology, Charles-Bruneau Cancer Center, Sainte-Justine Hospital, University of Montreal, 3175 Côte Sainte Catherine, Montreal, Canada H3T 1C5.
Ghadirian
P
P
Richer
C
C
Sinnett
H
H
Gandini
S
S
Perret
C
C
Lacroix
A
A
Labuda
D
D
Sinnett
D
D
D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D001943:Breast Neoplasms / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D002273:Carcinogens / Q000378:metabolism*; D002277:Carcinoma / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004781:Environmental Exposure; D005260:Female; D005602:France / Q000208:ethnology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008593:Menopause; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors
D002273:Carcinogens; D007527:Isoenzymes; D019363:Cytochrome P-450 CYP1A1; D019389:Cytochrome P-450 CYP2D6; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human; D005982:Glutathione Transferase