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Page 690 Alonso-Peña et al. Cancer Drug Resist 2019;2:680-709 I http://dx.doi.org/10.20517/cdr.2019.006

enzymatic activity . Mutations related to this gene are described in Table 3. A second enzyme involved
[95]
in 5-FU catabolism is dihydropyrimidinase (DHP gene symbol DPYS), which catalyzes the conversion of
dihydro-5,6-fluorouracil to fluoro-β-ureidopropionate. DHP deficiency caused by heterozygous missense
and nonsense polymorphisms in DPYS gene may increase 5-FU toxicity .
[96]
NAD(P)H quinone oxidoreductase 1 (NQO1) catalyzes the reduction of quinones and nitro derivatives using
NADP or NADPH as cofactors. NQO1 expression leads to a favorable position for the development of tumor
cells by protecting them from oxidative stress and chemotherapeutic agents, resulting in cancer progression
and chemoresistance, as has been described for HCC . In CCA, NQO1 plays a role in modulating sensitivity
[97]
of cancer cells to gemcitabine when given in combination with dicoumarol, which enhances gemcitabine
cytotoxicity in CCA cells with high NQO1 activity . The most prominent and frequent variant of NQO1
[98]
is c.609C>T (p.Pro187Ser), which has been associated to an increased risk of colorectal cancer and colorectal
adenoma and poor OS in non-small-cell lung cancer .
[99]
[100]
Phase II Enzymes
Germline pharmacogenetics: Cytidine deaminase (CDA) is the major enzyme of gemcitabine inactivation.
This enzyme catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine to uridine and
deoxyuridine, respectively. CDA, which is poorly expressed in liver tissue , presents several SNPs that
[101]
have been associated with higher expression and enzymatic activity of CDA and poorer disease outcome
in patients treated with gemcitabine. Among the most studied variants are two non-synonymous SNPs,
c.79A>C (p.Lys27Gln) and c.208G>A (p.Ala70Thr), and three SNPs in the CDA promoter region that possibly
affect CDA expression, c.-451G>A, c.-92A>G and c.-31delC. Another well-studied variant is the synonymous
SNP c.435C>T (p.Thr145=), located at exon 4 .
[102]
Somatic pharmacogenetics: The somatic mutation c.208G>A (p.Ala70Thr) decreases the activity of CDA in
pancreas, lung and mesothelium cancer, which has clinical impact in patients treated with gemcitabine,
cisplatin and 5-FU [87,91] . Moreover, c.208G>A has been associated with a reduced clearance of gemcitabine and
increased neutropenia when patients were co-treated with gemcitabine and 5-FU or platinum-containing
drugs . The impact of c.79A>C and c.435C>T in the clinical outcome of 126 advanced non-small-cell lung
[87]
cancer patients treated with gemcitabine–platinum-regimens has been evaluated . The results indicated
[103]
that patients with the AC genotype had significantly longer time to progression and OS than patients with
CC genotype.

Deoxycytidine kinase (DCK) catalyzes the first rate-limiting phosphorylation step in the activation of
deoxycytidine analogs. The combination of three mutations, c.511G>A (p.Glu171Lys), c.739G>A, (p.Glu247Lys)
and c.745G>A (p.Leu249Met) in DCK sensitizes a panel of cancer cell lines to treatment with gemcitabine .
[104]
Several SNPs have been suggested to affect glutathione S-transferases function and favor carcinogenesis. The
SNP c.-67C>T in the GSTA1 promoter, when expressed in hepatocytes, reduces GSTA1 expression. Moreover,
the TT genotype is more frequent in HCC than in healthy controls. In addition, GSTA1 expression is lower
in HCC than in healthy livers .
[105]

Sulfotransferases (SULT) catalyze the addition of a sulfonate moiety. Three human SULT families have been
identified: SULT1, SULT2 and SULT4 . SULT1A1 metabolizes brivanib, a drug used in phase III trials as
[106]
the first-line treatment of HCC . SULT1A1 is up-regulated in patients with HCC secondary to chronic
[107]
HBV infection . Table 4 shows the mutations in SULT1A1 observed in PLC. In order to elucidate the role
[108]
of these mutations in the chemoresistance of these tumors, further investigations are required.

Uridine 5’-diphospho glucuronosyl transferases (UGT) are a group of phase II drug-metabolizing enzymes
that catalyze the glucuronidation of xenobiotics and endogenous compounds . A reduction in the activity of
[39]