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Alonso-Peña et al. Cancer Drug Resist 2019;2:680-709 I http://dx.doi.org/10.20517/cdr.2019.006 Page 687

c.734C>G S c Phe245Arg Moderate ND TCGA-LIHC TCGA
c.1500G>T S c Lys500Asn Moderate ND TCGA- TCGA
CHOL
c.745A>G S nc Ile249Val Moderate ND TCGA-LIHC TCGA
g.89073197A>G S nc Enhancer region ND Lower expression HepG2 [64]
cells
g.88924371A>G S nc Enhancer region ND Lower expression HepG2 [64]
cells
g.89189602G>A S nc Enhancer region ND Lower expression HepG2 [64]
cells
ABCG2RE1*2 S nc Enhancer region ND Lower expression HepG2 [64]
cells
g.89026428A>C S nc Enhancer region ND Higher expression HepG2 [64]
cells

Data obtained from referred literature and TCGA database. Functional consequences are based on VEP (Variant Effect Predictor;
https://www.ensembl.org/vep) impact: High means that the variant is supposed to cause a high disruptive impact in the protein, which
is likely to cause loss of function; Moderate means that the variant may be not disruptive, but results in a decrease effectiveness of
the encoded protein; Modifier is usually referred to non-coding variants, whose impact is difficult to determine, although they can be
involved in transcription or splicing changes. CCA: cholangiocarcinoma; HCC: hepatocellular carcinoma; ND: not described; TCGA: the
cancer genome atlas; TCGA-LIHC: the cancer genome atlas - liver hepatocellular carcinoma; TCGA-CHOL: the cancer genome atlas -
cholangiocarcinoma

The best known MRP2 (ABCC2) variants are c.-24C>T, c.1249G>A (p.Val471Ile) and c.3972C>T (p.Ile1324=).
These frequent variants have been associated with higher chemoresistance and reduced survival rate in many
different tumors, including HCC and CCA [61,65-67] . Some combinations of these variants in homozygosis are
more sensitive to miR-379-induced ABCC2 mRNA down-regulation, leading to lower MRP2 expression .
[68]
Moreover, expression of the c.1249G>A variant has been associated to enhanced MRP2-mediated sorafenib
efflux [59,69] .

Owing to its high expression levels, MRP3 (ABCC3) plays a key role in the MDR phenotype of CCA [48,70]
and is also involved in the poor response of HCC to sorafenib . The SNP c.-211C>T, which is also present
[71]
in healthy liver, alters ABCC3 promoter activity although its functional repercussion is controversial [62,63] .
Regarding MRP4 (ABCC4) and MRP5 (ABCC5), some polymorphisms that modify their stability and
substrate specificity have been described [72-74] . Nevertheless, their relationship with drug resistance in PLCs
remains unknown.

A role of BCRP in HCC chemoresistance has been reported , whereas this is not clearly elucidated in the
[75]
case of CCA . In healthy liver tissue, the expression of c.421C>A (p.Gln141Lys) variant correlates with
[76]
low BCRP protein levels . In addition, several SNPs that modify enhancer activity at the ABCG2 gene
[77]
locus have been reported . Four of these variants (g.89073197A>G, g.88924371A>G, g.89189602G>A and
[64]
ABCG2RE1*2, which is a combination of g.88923906G>A, g.88924176C>T and g.88924371A>G) decreased
the promoter activity and hence reduced gene expression, contrary to g.89026428A>C that is associated with
increased BCRP activity. Moreover, other genomic variants (g.89073197A>G and g.88924371A>G) increase
the ability of ABCG2 gene to bind to nuclear proteins in human hepatoma HepG2 cells .
[64]

Mutations affecting drug metabolism (MOC-2)
Changes in drug metabolism, either by reduction in the activation of prodrugs or increased inactivation of
active agents, can contribute to chemoresistance. The enzymes involved in MOC-2 participate in either phase
I reactions (oxidoreduction of substrates) or in phase II (conjugation with polyatomic groups) processes .
[39]
As many anticancer agents are administered as prodrugs, they require metabolic activation by phase I
enzymes. Thus, the presence of variants in genes encoding these enzymes is relevant in cancer therapy,
because they may reduce the efficacy of several antitumor drugs and increase their adverse effects . In
[78]