PEER-REVIEW | ANTI-AGEING MEDICINE | Genotypes and risk for breast cancer
Quantification of the relative risk of sporadic breast cancer on the basis of the impact of different genetic polmorphisms involved in steroidal hormone metabolism
Analysed risk alleles CYP1A1*2A CYP1B1*3
CYP17A1(T34C) GSTM1 GSTT1
SULT1A1*2 COMT(V158M)
Oestrogen receptor (ER) Oestrogen receptor (ER)
Genotype vt/vt
wt/wt wt/vt vt/vt
wt/wt wt/wt wt/vt Xx Pp
Impact +1 0 0
+2 0 0
+2 0 0
Values from 1 to 4 are assigned to the impact of a given polymorphism on the basis of values of relative risk published in the literature
Impact Interpretation 0
1
2 3 4
Reference Weak
Medium Strong
Very strong
decreased (-) increased (+) 1
Relative risk 1
0.7 - <0.9 1.1 - <1.5 0.4 - 0.7
>7.0 1.5 - <3.0
0.2 - 0.4 3.0 - <7.0 <0.2
Mrs. Modele, Nicole (Lab-no: 1199991000)
neutralised (in the case of GST genotype decreased predictive activity)13–15
.
Methylation Catechol oestrogens 2-OH and 4-OH are readily oxidised to semiquinones and quinones, which are damaging to DNA and can even promote carcinogenesis via the generation of reactive oxygen species (ROS). This oxidation can be minimised through good methylation of catechol oestrogen by the (catechol-O-methyltransferase) enzyme16, 17
COMT . Evidence is
accumulating to suggest that low activity of the COMT genotype leads to higher levels of depurinating oestrogen-DNA adducts that can induce mutation and initiate cancer. The COMT genotype remained the most significant determinant for breast cancer development and was associated with a four-fold increase in risk16, 17
.
Normal folate status appears to be of particular importance in this context, because an increasing number of COMT low-activity alleles is significantly associated with an increased breast cancer risk in women with below average levels of folate18
. Recent data suggest that methylation of 4-OH makes
this metabolite significantly less active, while production of 2-methoxyestrone may manifest beneficial properties by inhibiting breast cancer19
. As there is great variation
throughout the population, identifying the presence of this SNP is vital to enhance good methylation properties in the body. Sulfation is an additional component of endogenous oestrogen detoxification, especially as methoxy
52 ❚ January/February 2013 |
prime-journal.com Quinones GSTM Mercapturates Sulfated E1
Glucuronated E1
E3 E2 E3 SHBG 4-OH COMT 4-MeO E1 CYP1A1 2-OH COMT 2-MeO Androgens CYP17A1 CYP19A1
SNPs involved in oestrogen detoxification
Figure 3 Combination of the genotypes with an increased risk for sporadic breast cancer (COMT + GSTM1; CYP1A1 + GSTM1)
metabolites. The presence of the SULT1A1 allele combined with regular alcohol consumption, tobacco smoking, weight excess and late menopause increase the relative risk of both bronchial and breast cancer20 Glucuronidation, as a key phase II detoxification,
.
allows glucuronic acid to be conjugated with oestrogen and be eliminated by the body. In the case of the presence of pathogenic intestinal bacteria, which can produce β-glucuronidase, some of the oestrogen can re-enter circulation by uncoupling the bond between oestrogen and glucuronic acid, leading to an increased enterohepatic circulation and an increased incidence of breast cancer21
. Identifying oestrogen metabolism and their
Figure 4 Oestrogen detoxification and SNPs involved
metabolites in each patient are the most important factors in making a decision as to whether or not HRT should be prescribed (Figure 4).
Identifying
oestrogen metabolism and their metabolites in each patient are the most important factors in making a decision as to whether or not HRT should be prescribed.
CYP1B1
CYP3A4
SULT-1A1 UGT
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