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Table 2: Overview of 33 additional SNPs located in genes involved in the pharmacokinetics or pharmacodynamics of the FEC regimen
Genes
Name
Function of the gene product
Variant allele (rs number,
position, amino acid change)
Pharmacokinetic or pharmacodynamics effect
ABCBI/MDR1
Multidrug resistance 1
Drug transporter implicated in energy dependent
transport of cytotoxic agents out of the cell
rs2032582 c.2677G>T/A Ala893Ser/Thr
Selected because missense mutations are likely to affect gene
function.
NCF4*
Neutrophil cytosolic factor 4
Component of the NADPH-oxidase, a
multicomponent enzyme system responsible for the
oxidative burst in which electrons are transported
from NADPH to molecular oxygen, generating
reactive oxidant intermediates.
rs1883112 g.-212A>G N/A
The rs1883112 SNP is responsible for downregulation of the
NADPH-oxidase subunit NCF4 and has previously been
associated with cardiotoxicity after anthracycline therapy
(Wojnowski et al4).
ABCC2/MRP2
Multidrug resistance-associated
protein 2
Drug transporter implicated in energy dependent
transport of cytotoxic agents out of the cell
rs2804402 -1019T>C 5’-flanking
Selected because missense mutations are likely to affect gene
function.
Dihydropirymidine
dehydrogenase
Enzyme involved in degradation of pyrimidine and
uracil analogues during 5-FU chemotherapy
RAC2*
Ras-related C3 botulinum toxin
substrate 2
Plasma membrane-associated small GTPase that
binds to a variety of effector proteins to regulate
cellular responses. RAC2 augments the production
of reactive oxygen species by NADPH oxidase
rs13058338 7508T>A N/A
This variant has previously been associated with cardiotoxicity
after anthracycline therapy (Wojnowski et al4).
CYBA*
Cytochrome b-245, alpha
polypeptide
Critical component of the membrane-bound
oxidase of phagocytes that generates superoxide.
CYBA associates with NOX3 to form a functional
NADPH oxidase constitutively generating
superoxide.
rs4673 c.214C>T His72Tyr
The rs4673 T-allele in CYBA, coding for p22phox, has previously
been associated with cardiotoxicity after anthracycline therapy
(Wojnowski et al4).
CYP3A4
Cytochrome P450, family 3,
subfamily A, polypeptide 4
Enzyme involved in the activation pathway of
cyclophosphamide by hydroxylating
cyclophosphamide to 4-hydroxycyclophosphamide
rs4986910 c.1334T>C Met445Thr
Selected because missense mutations are likely to affect gene
function.
SLC28A3*
Solute carrier family 28,
member 3
Sodium-dependent transporter involved in the
homeostasis of endogenous nucleosides.
rs7853758 c.1381G>A Leu461Leu
This synonymous variant previously been associated with
anthracycline-induced chemotherapy in children (Visscher et al3).
GSTA1
Glutathione S-transferase alpha
1
Enzyme involved in the detoxification of
cyclophosphamide by conjugation of
cyclophosphamide metabolites
rs3957356 g.52608670T>C N/A
The rs3957357 was predictive for rituximab-CHOP outcome in
large B-cell lymphoma (Rossi et al40).
GSTP1
Gluthathione S-transferase pi 1
Enzyme involved in the detoxification of
cyclophosphamide by conjugation of
cyclophosphamide metabolites
rs1138272 c.341C>T Ala114Val
The rs1138272 was predictive in the adjuvant and metastatic
setting of colorectal cancer patients treated with the 5fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen (Cecchin
et al41).
ABCG2*
ATP-binding cassette,
Drug transporter implicated in energy dependent
rs2231137 c.34G>A Val12Met
Variant genotypes for rs2231137 in ABCG2 were associated with
rs17222723 c.3563T>A Val1188Glu
rs2273697 c.1249G>A Val417Ile
DPD
rs1801159 c.1627A>G Ile543Val
rs1801160 c.2194G>A Val732Ile
Selected because missense mutations are likely to affect gene
function.
rs1801265 c.85T>C Cys29Arg
rs55785340 c.664A>G Ser222Pro
rs3957357 -69G>A N/A
subfamily G, member 2
transport of cytotoxic agents out of the cell
significantly improved survival and increased odds for toxicity
after anthracycline-based therapy (Hampras et al42).
ALDH3A1*
Aldehyde dehydrogenase 3
family, member A1
Enzyme involved in the detoxification pathway of
cyclophosphamide by oxidation of
aldophosphamide
rs2228100 c.985C>G Pro329Ala
In high dose cyclophosphamide treated patients, rs2228100 was
associated with increased hemorrhagic cystitis (ekhart et al43).
CYP2C8*
Cytochrome P450, family 2,
subfamily C, polypeptide 8
Enzyme involved in the activation pathway of
cyclophosphamide by hydroxylating
cyclophosphamide to 4-hydroxycyclophosphamide
rs72558196 c.475delA Thr159 Frameshift
SNPs in CYP2C8 have been reported to have an impact on
rosiglitazone intake and the urinary excretion of
dihydroxyeicosatrienoic acids (Kirchheiner et al44).
rs10509681 c.1196T>C Lys399Arg
rs11572080 c.416G>A Arg139Lys
rs56489507 c.792T>C/G Ile264Ile/Met
Cytochrome P450, family 2,
subfamily C, polypeptide 9
Enzyme involved in the activation pathway of
cyclophosphamide by hydroxylating
cyclophosphamide to 4-hydroxycyclophosphamide
rs1057910 c.1075A>C Ile359Leu
Cytochrome P450, family 2,
subfamily C, polypeptide 19
Enzyme involved in the activation pathway of
cyclophosphamide by hydroxylating
cyclophosphamide to 4-hydroxycyclophosphamide
rs4244285 c.681G>A Pro227Pro
CYP3A5*
Cytochrome P450, family 3,
subfamily A, polypeptide 5
Enzyme involved in the activation pathway of
cyclophosphamide by hydroxylating
cyclophosphamide to 4-hydroxycyclophosphamide
rs776746 c.219-237G>A Splice variant
The rs776746 SNP in CYP3A5 is the most common cause of loss
of hepatic CYP3A5 expression, which results in protein truncation
due to defective splicing and retention of an intronic site carrying a
premature termination codon. Thus, only people with at least one
CYP3A5*1 allele express functional CYP3A5 (Van Schaik et al
48
).
XRCC1
X-ray repair complementing
defective repair in Chinese
hamster cells 1
The base excision repair protein capable to restore
DNA single-strand breaks emerged due to exposure
to ionizing radiation and alkylating agents
rs25489 c.839G>A Arg280His
Selected because missense mutations are likely to affect gene
function.
UGT2B7*
UDP-glucuronosyltransferase 2
family, polypeptideB7
Enzyme responsible for the formation of epirubicin
glucuronide, which is the most important
inactivation pathway of epirubicin
rs7439366 c.802T>C or UGT2B7*2
UGT2B7 genetic polymorphisms are associated with the
withdrawal symptoms in methadone maintenance patients (Tian et
al49).
CYP2C9*
CYP2C19*
rs1799853 c.430C>T Arg144Cys
rs4986893 c.636G>A Trp212STOP
Tyr268His
rs7662029 -327A>G N/A
In vitro studies have shown that the rs1057910 variant causes an
Ile359Leu substitution in the catalytic site of the CYP2C9 enzyme
and is less active than the wild-type allele (Bosch et al45).
CYP2C19*2 was correlated with reduced cyclophosphamide
elimination and had a higher probability of developing end-stage
renal disease when treated with cyclophosphamide for lupus
nephritis (Timm et al46 and Takada et al47). CYP2C19*2 was also
correlated with tendency for longer cyclophosphamide half-life in
103 patients treated for non-Hodgkin’s lymphoma (Nakajima et
al13).
rs7668282 -79T>C N/A
rs12233719 c.211G>T or UGT2B7*3
Ala71Ser
XRCC3*
X-ray repair complementing
defective repair in Chinese
hamster cells 3
Involved in the homologous recombination repair
pathway of double-stranded DNA, thought to repair
chromosomal fragmentation, translocations and
deletions
rs861534 g.104168701G>A N/A
The rs861534 SNP was associated with longer OS in early breast
cancer patients receiving adjuvant chemotherapy. In the patient’s
subgroup receiving anthracyclines XRCC3 rs861534 was
associated with improved OS (Marcos et al50).
Legend to Table 2: The rs2273697, rs11572080, rs56489507 and rs3957356 SNPs failed genotyping on Sequenom MassARRAY. The rs861534 variant also failed, but was captured
by genotyping the synonymous SNP rs861539. * Selection of extra genes based on current knowledge of genes involved in the metabolism of 5-fluorouracil, epirubicine, and
cyclophosphamide (see also webappendix 2). SNP in DNA repair pathways, which are activated after DNA damage by chemotherapy, can potentially influence metabolism and
toxicity but also efficacy of the chemotherapy.
Legend to Table 1 and 2:
The SNP selection for the FEC regimen has been extensively described in table 1 and 2 of our previous paper
Vulsteke C, Lambrechts D, Dieudonné AS et al: Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological
toxicity in breast cancer patients receiving (neo-) adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC). Ann Oncol 24(6):151325, 2013.
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