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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 685

Somatic pharmacogenetics: Although downregulation of OATP1B1 and OATP1B3 in HCC, CCA and
advanced metastatic liver tumors has been reported , no information on somatic mutations affecting these
[27]
transporters in PLCs is available. Regarding SLC22A genes, several variants of OCT1 have been identified
in PLCs, including SNAs and splicing variants . Among them, several inactivating variants, such as
[24]
c.262T>C (p.Cys88Arg), c.566C>T (p.Ser189Leu), c.659G>T (p.Gly220Val) and c.859C>G (p.Arg287Gly), were
detected with a higher frequency in HCC and CCA than in the adjacent non-tumor tissue. In vitro studies
showed that these and other OCT1 mutations found in PLCs, such as c.262delT (p.Cys88Alafs*16) and
c.181delCGinsT (p.Arg61Serfs*10), result in lower sorafenib uptake and hence poorer induced cytotoxicity.
Short non-functional SLC22A1 mRNA variants have also been detected in other malignancies, such as
glioma and chronic myeloid [29-31] and lymphocytic leukemia. Moreover, not only mRNA abundance but
[32]
[28]
also the correct localization of OCT1 at the plasma membrane is important for the response of HCC patients
to sorafenib . The reduction in SLC22A1 expression has been associated with advanced tumor stages and
[33]
shorter survival of patients with HCC or CCA .
[34]
[35]
Evidence for reduced OCT3 expression in HCC and CCA has also been found. In vitro experiments in
cisplatin resistant hepatoma cells have shown reduced OCT3 expression in these cells, which resulted in
lower cisplatin uptake, whereas induced OCT3 overexpression restored the sensitivity of these cells to
cisplatin . Whether, in addition to changes in transcription, there are associated somatic mutations is not
[36]
known.

Some studies have described a correlation between low SLC29A1 expression and poor prognosis in HCC
patients , whereas up-regulation of SLC29A2 has been associated with advanced stages, vascular invasion
[37]
and poor survival in these patients . However, no further research on somatic mutations affecting these
[38]
transporters has been reported.

Genetic variants in genes involved in drug export (MOC-1b)
ABC transporters mediate the active efflux of a large variety of compounds, including antitumor drugs.
Thus, a high expression/activity of these pumps induces a decrease in intracellular drug concentrations that
plays an important role in the MDR phenotype of PLCs . Several mutations affecting these transporters
[39]
may determine the response of HCC and CCA to their substrates [Table 2].

Germline pharmacogenetics: Concerning germline mutations, only those affecting ABCG2 (c.34G>A;
p.Val12Met and the intron variant g.89078924T>C) deserve to be mentioned. Both in vitro and in vivo [41]
[40]
studies have demonstrated the ability of the breast cancer resistance protein (BCRP) encoded by ABCG2 to
export sorafenib with higher affinity than MDR1 . Hence, when present in homozygosis, these mutations
[42]
have been associated with lower exposure of extratumor tissues and a better response to sorafenib .
[43]
Somatic pharmacogenetics: MDR1 (ABCB1) also known as P-glycoprotein, is involved in the pharmacokinetics
of many drugs , including sorafenib , which is consistent with the fact that MDR1 expression has been
[44]
[42]
inversely correlated with HCC response to pharmacological treatment [45,46] . Interestingly, MDR1 has been
found highly expressed in CCA biopsies and cell lines . Regarding its genetic variability, more than
[48]
[47]
60 SNAs for ABCB1 have been described . The presence of the synonymous SNP c.3435C>T (p.Ile1145=)
[49]
in heterozygous patients has been associated with increased levels of MDR1 and higher risk of HCC
recurrence . This mutation has also been related to a lower exposure to sorafenib in HCC patients [43,51] .
[50]
Proteins encoded by ABCC genes, also known as multidrug resistance-associated proteins, are involved
in PLC chemoresistance [52-56] . The presence of the polymorphism c.-1666G>A in MRP1 (ABCC1) has been
correlated with low promoter transcriptional activity . The opposite occurs in the case of the variant c.-
[57]
260G>C . Moreover, poor outcome and shorter survival have been described in patients with PLC carrying
[58]
the c.-1666G>A variant .
[57]