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susceptibility of breast cancer was almost three-fold increased among women with a BMI
greater than 24 kg/m
2
>With the exception of the BMI under evaluation, ORs and 95% CIs
adjusted for other variables; 2.81 (1.38-5.74)@. The results showed that the
CYP1B1*3
variant which is predicted to be associated with higher activity was positively related to the
susceptibility of breast cancer and was specific to women with a BMI greater than 24
kg/m
2
.
Catechol-
O
-methyltransferase (
COMT
; E.C.2.1.1.6.) is one of several phases II
enzyme, which is responsible for the detoxification of catecholamine including 2-CE and 4-
CE by
O
-methylation. The level of
COMT
activity is controlled by a common genetic
polymorphism being homozygous for a low activity allele termed
COMT-L
(V158M) >10@.
Reduced
COMT
activity might increase the risk of cancer due to accumulation of CE,
which causes oxidative DNA damage >6@. The
COMT-H
and
COMT-L
alleles were detected
by minor modifications of the methods described by Lachman et al. >10@. In the case of
COMT
, the allele frequency of high activity
COMT-H
allele and low activity
COMT-L
allele was found to be 0.58 and 0.42 in the cases. There was no significant difference in
susceptibility for breast cancer development between patients with
COMT-L
(V158M) and
COMT-H
alleles >the adjusted OR; 0.86 (95% CI 0.46-1.60, p=0.63)@, and susceptibility
was not affected by menopausal status, BMI, and other susceptibility factors.
Manganese containing superoxide dismutases (
MnSOD;
EC 1.15.1.1), the only
known superoxide scavenger in mitochondria, may be particularly important for antioxidant
defense and hence production of reactive oxygen radicals (ROS) >6@. A one base pair
transition (ToC) leads to a ValoAla amino acid change at codon 16 in the -9 position of
signal sequence of
MnSOD
, produces a conformational change in the helical structure of
the protein. This change may decrease the efficiency of transport into mitochondria >11@.
Because
MnSOD
is a major enzyme involved in the scavenging of free radicals, ROS
generated by estrogens and their metabolites may be involved in breast cancer etiology. The
MnSODVal
and
MnSODAla
alleles were detected by minor modifications of the methods
described by Shimoda-Matsubayashi et al. >11@. The frequencies of Val / Val, Val / Ala,
Ala / Ala genotypes were found to be 0.33, 0.45, 0.22, respectively in cases. There was no
significant difference in the frequency of the
MnSOD Ala
allele between cases and controls
>the adjusted OR; 0.86 (95% CI 0.43-1.72, p=0.67@.
The analysis of susceptibility of breast cancer associated with the
MnSOD
genotypes stratified by
COMT-L
and
CYP1B1
alleles was performed. When
MnSOD Ala
allele was combined with either
COMT-HL
and
COMT-LL
or
CYP1B1*1/*3
and *
3/*3
genotypes and all gene-gene interaction together, the risk for developing breast cancer was
not significantly increased OR 1.04 (95% CI= 0.95-1.26), OR 1.38 (95% CI= 0.92-2.85)
and OR 0.90 (95% CI= 0.68-1.19), respectively. The postmenopausal breast cancer
susceptibility was increased in patients with
MnSOD Ala
,
CYP1B1*1
and
COMT-L
variants
OR: 1.26 (95% CI= 0.93-1.72). However, the susceptibility for developing breast cancer
approaches significance in patients with a BMI greater than 24 kg /m
2
>OR: 1.42 (95% CI=
1.04-1.93)@, when
MnSOD Ala
was combined with either
CYP1B1*1
and
COMT-L
genotypes. This finding suggests that
MnSOD Ala
,
CYP1B1*1
and
COMT-L
variants are
involved in the susceptibility to breast cancer in certain women.
Many arylamine and hydrazine drugs, as well as for a number of known carcinogens
aromatic and the heterocyclic amines present in the diet, cigarette smoke and the
environment can be either detoxified by arylamine
N
-acetyltransferase (
NAT2;
EC 2.3.1.5)
and eliminated from the body or bioactivated to metabolites that have the potential to cause
toxicity and ҡҏor cancer >12@. Thirteen different SNPs in
NAT2
gene occurring single or in
combination define numerous alleles (15-20) associated with decreased expression, low
activity, enzyme instability and biochemical phenotypes ranging from slow to fast
