Table 1: List of 26 selectedSNPsin 16 genes correlating with toxicity/clinical outcome of anthracycline based regimens (5-fluorouracil, anthracyclines, and cyclophosphamide) based on a Pubmed-based literature search.

Genes / Name / Function of the gene product / Variant allele (rs number, position, amino acid change) / Effect of the polymorphism on the toxicity of drug therapy and clinical outcome
ABCBI/MDR1 / Multidrug resistance 1 / Drug transporter implicated in energy dependent transport of cytotoxic agents out of the cell / rs1045642c.3435T>CIle1145Ile / Correlation of TT-genotypes with complete clinical response to neo-adjuvant doxorubicin-based chemotherapy in locally advanced breast cancer (Kafka et al1).
ABCC1/MRP1 / Multidrug resistance-associated protein 1 / Drug transporter implicated in energy dependent transport of cytotoxic agents out of the cell / rs3743527g.16235681C>TN/A and rs246221c.825T>CVal275Val
rs4148350g.16170477G>TN/A
rs45511401c.2012G>TVal671Gly / The rs3743527TT-genotype andrs3743527TT with rs246221TC/TT genotype combinations are associated with lower left ventricular fractional shortening after anthracyclines (Semsei et al2).
The variant T-allele of rs4148350protects against anthracycline-induced cardiotoxicity(Visscher et al3).
Carriers of the MRP1rs45511401 T-allele are predisposed to acute anthracycline induced cardiotoxicity (Wojnowski et al4).
ABCC2/MRP2 / Multidrug resistance-associated protein 2 / Drug transporter implicated in energy dependent transport of cytotoxic agents out of the cell / rs8187710c.4544G>A Cys1515Tyr / A-allele carriers predispose to acute anthracycline-induced cardiotoxicity (Wojnowski et al4).
DPD / Dihydropirymidine dehydrogenase / Enzyme involved in degradation of pyrimidine and uracil analogues during5-FU chemotherapy / rs3918290c.1905+1G>Asplice variant / Patients with rs3918290 variant allelsare well established to be at increased risk for 5-Fluorouracil associated severe toxicity(Van Kuilenburg et al5-7, Takimoto et al8, Raida et al9, Morel et al10).
MTHFR / Methylenetetrahydrofolate reductase NAD(P)H / Enzyme responible for the metabolisation of vitamin B9 (folate), which is required for DNA synthesis / rs1801133c.677C>TAla222Val
rs1801131c.1298A>CGlu429Ala / The variant T-allele increased chemosensitivity of colon and breast cancers to 5-Fluorouracil, but decreasedchemosensitivity of breast cancer cells to methotrexate(Sohn et al11).
The rs1801133 T- and rs1801131 C-alleles are linked to clinical response after 5FU(Etienne-Grimaldi et al12).
CYP2B6 / Cytochrome P450, family 2, subfamily B, polypeptide 6 / Enzyme involved in the activation pathway of cyclophosphamide by hydroxylation to 4-hydroxycyclophosphamide / g.-2320T>C, g.-750T>C and g.15582C>T (CYP2B6*1B, CYP2B6*1G, CYP2B6*13B)
rs8192709c.64C>TArg22Cys (CYP2B6*2);rs2279343c.785A>GLys262Arg (CYP2B6*4);rs3745274c.516C<T Gln172His (CYP2B6*6)
rs3211371c.1459C>TArg487Cys (CYP2B6*5) / Severe leucocytopenia related to the CYP2B6*1B, CYP2B6*1G, CYP2B6*13B variants in breast cancer patients treated with cyclophosphamide. All 3 variants are highly linked. (Nakajima et al13).
Carriers of the T allele of rs8192709 wereassociated with a higher rate of hemorrhagic cystitis and oral mucositis in leukemia patients receiving cyclophosphamide, methotrexate and busulfan (Rocha et al14).
More dose delays due to toxicity in CYP2B6*2 and CYP2B6*5 breast cancer patients receiving doxorubicine and cyclophosphamide (Bray et al15).
CYP3A4 / Cytochrome P450, family 3, subfamily A, polypeptide 4 / Enzyme involved in the activation pathway of cyclophosphamide by hydroxylation to 4-hydroxycyclophosphamide / rs2740574 -392A>GN/A (CYP3A4*1B) / Women with at least oneCYP3A4*1B variant allele had significantly worse DFSafter adjuvant cyclophosphamide-containing chemotherapy (Gor et al16).
GPX4 / Glutathione Peroxidase 4 / Enzyme involved in the anti-oxidant defense / rs713041c.767T>CLeu220Leuand rs757229g.1042114G>CN/A / Variant alleles of rs713041 and rs757229 were associated with all-cause mortality.Both SNPs were correlated (Udler et al17).
GSTA1 / Glutathione S-transferase alpha 1 / Enzyme involved in the detoxification of cyclophosphamide by conjugation of CP metabolites / GSTA1*B / Study in breast cancer patients treated with cyclophosphamide-containing regimen. Patients with GSTA1*B/*B genotypes had a longer 5 years survival and a reduced hazard of death (Sweeney et al18).
GSTP1 / Gluthathione S-transferase pi 1 / Enzyme involved in the detoxification of cyclophosphamide by conjugation of CP metabolites / rs1695c.313A>GIle105Val / Systemic Lupus Erythematosus patients carrying one or two G-alleles had an increased risk of myelotoxicityand gastro-intestinal toxicity when treated with pulsed high-dose cyclophosphamide therapy(Zhong et al19).
FGFR4 / Fibroblast growth factor receptor-4 / Tyrosine-kinase receptor involved in a number of cellular processes such as cell growth, differentiation, migration and angiogenesis / rs351855c.1162C>TGly388Arg / In node-positive patients, receiving CMF adjuvant chemotherapy, the rs351855 T-allele was associated with poor DFSand OS. This association was attributable to poor therapy response in the rs351855 T-allele carriers(Thussbas et al20).
NQO1 / NAD(P)H: quinone oxidoreductase 1 / The NQO1 enzyme is implicated in protection against oxidative stress and carcinogenesis, including stabilization of the p53tumor suppressor / rs1800566c.559C>TPro187Ser / Poor survival rate in epirubicin-treated breast cancer patients due to an impaired response to epirubicin in carriers of the variant T-allele (Fagerholm et al21).
SOD2 / Manganese superoxide dismutase-2 / A mitochondrial enzyme that catalyzes the formation of H2O2 from superoxide radicals generated by chemotherapy / rs4880 c.47T>C Val16Ala / Risks of disease progression and death in metastatic breast cancer patients, receiving high dose cyclophosphamide based regimens followed by autologous stem cell transplantation, were increased inrs4880 TT-genotype carriers (Bewick et al22).
TS / Thymidylate synthase / Enzyme implicated in the conversion of deoxy-uridine monophosphate (dUMP) into deoxy-thymidine monophosphate (dTMP), which is essential in DNA synthesis / rs11280056g.673447delAAGTTAN/A; rs34743033 28-bp tandem repeatTSER*1, TSER*2, TSER*3 / A poor response rate to 5-FU for neo-adjuvant rectal or metastatic colorectal cancer patients with high TSER copy numbers (TSER*3/TSER*3) (Marsh et al23).
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 / rs25487c.1196G>AArg399Gln / Carriers of the rs25487 AA-genotype exhibited reduced risk for recurrence/death (Sun et al24, Jaremko et al25).
XPD/ERCC2 / Excision repair cross-complementing rodent repair deficiency, complementation group 2 / Enzyme involved in nucleotide excision repair of DNA by opening DNA around the damage / rs13181c.2251T>G Lys751Gln
rs1799793c.934G>A Asp312Asn / Patients with Gln751 allele have a significantly lower respons to FOLFOX-4 treatment and shorter PFS and OS (Lai et al 26).
Severe neutropenia was associated with XPD 312 Asp/Asn in ovarian cancer patients receiving cisplatin-cyclophosphamide regimen (Khrunin et al 27).

Legend to table 1:Since rs25487in XRCC1could not be genotyped, we selected the rs25486 variant, which is in full linkage disequilibrium with rs25487, for genotyping. Since rs713041 and rs757229in GPX4were highly linked, we only selected rs757229 for genotyping. Likewise, since CYP2B6*1B, CYP2B6*1G, CYP2B6*13B were highly linked, we only selected CYP2B6*1B for genotyping. Of all 26 selectedSNPs we attempted to genotype, the following 5SNPs failed genotyping: rs3211371, rs4880, GSTA1*B, CYP2B6*1B and TSER.DFS, Disease Free Survival; CMF, cyclophosphamide-methotrexate-fluorouracil; OS, overall survival; PFS, progression free survival.