1
Supplementary Tables
Table S1:Genes and Polymorphisms in Phase I and II Enzymes Investigated for a Potential Role in Breast Cancer Risk Associated with Menopausal Hormone Therapy (HT) Use
Genes and functional roleof the encoded enzyme / dbSNP / DNA change
(* nomenclature) / Protein change / Functional consequence / Potential risk association
Phase I metabolism
CYP1A1
encodes enzyme which catalyzes 2-, 4- and 16-hydroxylation of 17-beta-estradiol and formation of 4-hydroxy estrone and 2-hydroxyestrone [1-3] / rs1799814 / 2452_C>A
CYP1A1*4 / Thr461Asn / A allele encodes enzyme with decreased catalytic efficiency [4] / CYP1As, CYP1B and CYP2Cs in general - ambivalent:
Degradation of 17-beta estradiol may lead to lower estradiol levels with potential protective effects. Conversely, catechol estrogens, i.e., 2-hydroxy- or 4-hydroxy-estrogens, are unstable metabolites that can lead to generation of more reactive semiquinones and quinones and produce DNA-damaging reactive oxigenes. 4-hydroxy estrogens are equivalent in estrogenic potency but longer-acting than parent estrogen due to decreased dissociation from estrogen receptor [1;3;5;6].
considering HT use:
A allele causing decreased activity of the encoded enzyme may lead to decreased metabolism of estradiol. Therefore, A allele carriers at potentially increased risk, especially during HT use. Conversely, decreased activity may be protective since generation of reactive oxigenes is reduced.
rs1048943 / 2454_A>G
CYP1A1*2B / Ile462Val / G allele encodes enzyme with increased activity[7] / considering HT use:
G allele causing increased activity of the encoded enzyme may lead to increased metabolism of estradiol. Therefore, G allele carriers are at potentially decreased risk, especially during HT use. Conversely, increased activity may lead to thegeneration of reactive oxigenes.
rs4646903 / 3803_T>C
CYP1A1*2A / - / C allele associated with higher activity of the encoded enzyme [7;8] / considering HT use:
The C allele causes increased activity of the encoded enzyme may be leading to increased metabolism of estradiol. Therefore carriers of the C allele potentially have a decreased breast cancer risk especially during HT use. On the other hand increased activity potentially leads to thegeneration of reactive oxigenes.
CYP1A2
encodes enzyme which catalyzes 2-, 4- and 16-hydroxylation of17-beta-estradiol and formation of 16 alpha- estrone, 4-hydroxyestrone and 2-hydroxyestrone [1;3;9] / rs762551 / -164_A>C
CYP1A2*1F / - / C allele associated with reduced CYP1A2 activity in smokers [10] / considering HT use:
C allele causing decreased activity of the encoded enzyme may lead to decreased metabolism of estradiol. Therefore, C allele carriers are at potentially increased risk, especially during HT use. Conversely, decreased activity may be protective as generation of reactive oxigenes is reduced.
CYP1B1
encodes enzyme that catalyzes the addition of a
2-, 4- and 16-alpha-hydroxylation of 17-beta-estradiol and metabolism of estrogens to reactive catechols and catalyzes formation of catechol estrogens, predominantly 4-hydroxyestrogenes [1;3;6;11] / rs10012 / 142_C>G
CYP1B1*2 / Arg 48 Gly / G allele may increase CYP1B1 enzyme hydroxylation activity [12] / considering HT use:
G allele may increase activity of encoded enzyme, potentially leading to increased metabolism of estradiol and higher levels of catechol estrogens. G allele carriers may be at increased risk, particularly with HT use.
rs1056827 / 355_G>T
CYP1B1*2 / Ala 119 Ser / T allele may increase CYP1B1 enzyme hydroxylation activity [12;13] / considering HT use:
T allele may increase activity of encoded enzyme, potentially leading to increased metabolism of estradiol and higher levels of catechol estrogens. G allele carriers may be at increased risk, particularly with HT use.
rs1056836 / 4326_C>G
CYP1B1*3 / Leu432Val / G allele encodes enzyme with increased activity [12;14;15] / considering HT use:
G allele causes increased activity of encoded enzyme, potentially leading to increased metabolism of estradiol. G allele carriers are at potentially decreased risk, especially during HT use. Conversely, increased activity may bea risk factor due to increased generation of reactive oxigenes. Furthermore, 4-hydroxy estrogens with decreased dissociation from estrogen receptor causes increased gene expression.
rs1800440 / 4390_A>G
CYP1B1*4 / Asn453Ser / G allele encodes enzyme which catalyzes the 4-hydroxylation of estradiol moreefficiently [12] / considering HT use:
G allele causes increased activity of encoded enzyme, potentially leading to increased metabolism of estradiol. G allele carriers are at potentially decreased risk, especially during HT use. Conversely, increased activity may be a risk factor due to increased generation of reactive oxigenes. Furthermore, G allele may lead to increased formation of 4-hydroxy estrogens which have decreased dissociation from estrogen receptor.
CYP2C9
encodes enzyme which catalyzes 2- and16-alpha-hydroxylation of 17-beta-estradiol, and (to lower degree) 4-hydroxylation, leading to the formation of 16 alpha- estrone, 2-hydroxyestrone and 4-hydroxyestrone[16] / rs1799853 / 430_C>T
CYP2C9*2 / Arg 144 Cys / T allele encodes enzyme with approximately 12% enzymatic activity [17;18] / considering HT use:
T allele causing decreased activity of encoded enzyme may lead to decreased metabolism of estradiol. T allele carriers are at potentially increased risk, especially during HT use. Conversely, decreased activity may be protective as generation of reactive oxigenes is reduced.
rs1057910 / 1075_A>C
CYP2C9*3 / Ile 359 Leu / C allele encodes enzyme with approximately 5% enzymatic activity [19] / considering HT use:
C allele causing decreased activity of encoded enzyme may lead to decreased metabolism of estradiol. C allele carriers are at potentially increased risk, especially during HT use. Conversely, decreased activity may be protective as generation of reactive oxigenes is reduced.
CYP2C19
encodes enzyme which catalyses 17-beta-hydroxdehydrogenation and 16-alpha-hydroxylation of 17-beta-estradiol [20;21] / rs4244285 / 681_G>A
CYP2C19*2 / Pro227 spicing defect / A allele causes splicing defect leading to abrogated activity of the encoded enzyme[22;23] / considering HT use:
A allele causing abrogated activity of encoded enzyme may lead to decreased metabolism of estradiol. A allele carriers are at potentially increased risk, especially during HT use.
CYP3A4
encodes enzyme which catalyzes the 2-, 4- and 16-alpha-hydroxylation of 17-beta-estradiol and the formation of 16 alpha- estrone, 4-hydroxyestrone and 2-hydroxyestrone[24] / rs11773597 / -747_C>G
CYP3A4*1F / - / Functional relevance of this polymorphism unclear [25;26] / CYP3As in general - ambivalent:
Degradation of 17-beta estradiol may lead to lower estradiol levels and may be therefore protective for breast cancer. Conversely, catechol estrogens, i.e., 2-hydroxy- or 4-hydroxy-estrogens, are unstable metabolites potentially leading to generation of more reactive semiquinones and quinones and production of DNA-damaging reactive oxigenes. 4-hydroxy estrogens are equivalent in estrogenic potency but longer-acting than the parent estrogen due to decreased dissociation from estrogen receptor [27;28].
rs2740574 / -392_A>G
CYP3A4*1B / - / G allele hypothesized to be associated with lower expression of the encoded enzyme [29;30] / considering HT use:
G allele causing decreased expression of encoded enzyme may lead to decreased metabolism of estradiol. G allele carriers at potentially increased risk, especially during HT use. Conversely, decreased activity may be protective as generation of reactive oxigenes is decreased. Furthermore, the G allele may lead to reduced formation of 4-hydroxy estrogens which have decreased dissociation from estrogen receptor.
CYP3A5
encodes enzyme which catalyzes the 16-hydroxylation of17-beta-estradiol and (to lower degree) in 2- and 4- hydroxylation, leading to formation of 16-alpha- estrone, 4-hydroxyestrone and 2-hydroxyestrone[31] / rs28371764 / -74_G>A
CYP3A5*1C / - / Functional relevance of this polymorphism unclear [26]
rs776746 / 6986_G>A
CYP3A5*3C / - / A allele creates cryptic consensus splice site in the pre mRNAcausing truncated protein with loss of enzyme activity[26;32] / considering HT use:
A allele causing lower levels of encoded enzyme may lead to decreased metabolism of estradiol. A allele carriers are at potentially increased risk, especially during HT use. Conversely, decreased activity may be protective as generation of reactive oxigenes is decreased. Furthermore, A allele may lead to reduced formation of 4-hydroxy estrogens which have decreased dissociation from estrogen receptor.
CYP3A7
encodes enzyme involved in metabolism of testosterone, cortisol, dehydroepiandrosterone and dehydroepiandosterone 3-sulfate and catalyzes 16-alpha-hydroylation of estrone [3;33;34] / rs11568825 / -167_T>G
CYP3A7*1C / - / Polymorphism located in PXR responsive element and G allele is suggested to lead to increased expression of the encoded enzyme [32;33] / considering HT use:
G allele may lead to increased expression of encoded enzyme potentially causing increased metabolism of estradiol. G allele carriers are at potentially decreased risk, especially during HT use. Conversely, decreased activity may be protective as generation of reactive oxigenes is decreased.
rs2257401 / 26041_G>C
CYP3A7*2 / Thr 409 Arg / C allele encodes enzyme with increased catalytic activity [35] / considering HT use:
C allele leads to increased activity of encoded enzyme potentially causing increased metabolism of estradiol.
C allele carriers are potentially at decreased risk, especially during HT use. Conversely, decreased activity may be protective as generation of reactive oxigenes is decreased.
PhaseII metabolism
COMT
encodes enzyme which catalyzes conversion of catechol estrogens, 2- and 4-hydroxyestradiol to methoxyestrogens [36] / rs4680 / 472_A>G / Val 158 Met / G allele encodes enzyme with 2- to 4- fold increased activity in vitro[37-39] / considering HT use:
COMT has a protective role against carcinogenesis, with detoxification of catechol estrogens and one product, 2-methoxyestradiol, believed to inhibit proliferation and angiogenesis [40-42]. G allele increases activity of encoded enzyme, possibly resulting in increased metabolism of carcinogenic catechol estrogens. G allele carriers may be at decreased risk, particularly with HT use.
GSTM1
encodes enzyme involved in inactivation of catechol estrogen quinones. Catalyses glutathione conjugation of catechol estrogens quinones, the reactive intermediates of estrogen metabolism capable of binding to DNA [43] / n.a. / gene deletion
GSTM1*2 / - / No expression of GSTM1 / GSTs in general - ambivalent:
GSTs involved in metabolism of catechol estrogen quinones, but also a wide range of potential carcinogens, resulting in activation and detoxification. Therefore, GST gene deletion could be associated with either decreased or increased risk of cancer [44]
considering HT use:
Gene deletion may cause decreased metabolism of estrogens and, thus, increased estrogen levels potentially increasing risk for women using HT. Conversely, decreased activity may be protective as bioactivation of procarcinogens reduced.
GSTM3
encodes enzyme involved in inactivation of catechol estrogen quinones. Catalyses glutathione conjugation of catechol estrogens quinones, the reactive intermediates of estrogen metabolism capable of binding to DNA[43] / rs36120609 / 2654_delAGG
GSTM3*B / - / AGG deletion generates recognition site for YY1 transcription factor causing altered transcription [45] / considering HT use:
AGG deletion with increases in metabolism of estrogens resulting in decreases in estrogen levels may lead to decreased risk for women using HT. Conversely, increased activity may be a risk factoras bioactivation of procarcinogens increased.
GSTP1
encodes enzyme involved in inactivation of catechol estrogen quinones. Catalyses glutathione conjugation of catechol estrogens quinones, the reactive intermediates of estrogen metabolism capable of binding to DNA[43] / rs1695 / 313_A>G
GSTP1*B / Ile 105 Val / G allele encodes enzyme with increased activity [46;47] / considering HT use:
G allele may cause increased metabolism of estrogens and thus, decreased estrogen levels possibly resulting in decreased risk for women using HT. Conversely, increased activity may be a risk factoras bioactivation of procarcinogens is increased.
rs1138272 / 341_C>T
GSTP1*C / Ala 114 Val / T allele encodes enzyme with lower catalytic efficiency [48] / considering HT use:
T allele may cause decreased metabolism of estrogens and thus, increased estrogen levels possibly resulting in increased risk for women using HT. Conversely, decreased activity may be protective as bioactivation of procarcinogens is reduced.
GSTT1
encodes enzyme involved in inactivation of catechol estrogen quinones [49;50] / n.a. / gene deletion
GSTT1*2 / - / No expression of GSTT1 / considering HT use:
Gene deletion may cause decreased metabolism of estrogens and thus, increased estrogen levels possibly resulting in increased risk for women using HT. Conversely, decreased activity may be protective as bioactivation of procarcinogens is reduced.
SULT1A1
encodes enzyme that catalyzes sulfonation of estrogens to form water-soluble, biologically inactive estrogen sulfates leading to reduced levels of estrogens [51;52] / rs9282861 / 638_G>A
SULT1A1*2 / Arg 213 His / A allele encodes enzyme with reduced biological half-life causing lower levels of SULT1A1 activity [53;54] / SULTs in general - ambivalent:
Sulfonation generally considered detoxification reaction, but several SULTs, particularly SULT1A1, involved in bioactivation of certain procarcinogens, including heterocyclic amines and polycyclic aromatic hydrocarbons[55;56].
considering HT use:
A allele may be associated with decreased metabolism of estrogens and thus, increased estrogen levels possibly increasing risk for women using HT. Conversely, decreased activity may be protective since bioactivation of procarcinogens is reduced.
UGT1A1
encodes enzyme involved indetoxification of catechol estrogens[49] / n.a. / (TA)n TAA repeat
UGT1A1*1 (n=6)
UGT1A1*28 (n=7)
UGT1A1*36 (n=5)
UGT1A1*37(n=8) / - / Promoter activity decreases with increasing number of (TA) [57-59] / UGTs in general - protective:
Glucuronidation generally considered detoxification reaction [43;60]
considering HT use:
UGT1A1*1 and UGT1A1*36 associated with increased promoter activity and thus, increased metabolism of estrogens. Decreased levels of estrogens and mutagenic estrogen metabolites may reduce overall and HT-associated breast cancer risk.
UGT1A6
encodes enzyme metabolising sex hormones to inactive compounds [43] / rs6759892 / 19_T>G
UGT1A6*2 / Ser 7 Ala / G allele leads to decreased mRNA level but reports on functional consequence of polymorphism are controversial. Linkage of 19 G and TA repeat of UGT1A1 makes an association with decreased activity plausible [61-64] / considering HT use:
The G allele is may be associated with decreased metabolism of estrogens and thus, increased estrogen levels causing increased risk for women using HT.
rs2070959 / 541_A>G
UGT1A6*2 / Thr 181 Ala / G allele in linkage with 19 G and TA repeat of UGT1A1. Therefore, decreased activity possible [65] / considering HT use:
The G allele is may be associated with decreased metabolism of estrogens and thus, increased estrogen levels possibly increasing risk for women using HT.
UGT2B7
encodes enzyme which catalyzes glucuronidation of catechol estrogens [43;66] / rs7439366 / 802_T>C / Tyr 268 His / No functional consequence of this polymorphism known [67] / considering HT use:
The G allele is may be associated with decreased metabolism of estrogens and thus, increased estrogen levels possibly increasing risk for women using HT.
n. a. not available
24.11.08
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