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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 693

c.-17C>A S nc 5’UTR Modifier ND TCGA-LIHC TCGA
g.177608775T>C S nc Intron ND Decreased HCC patients [118]
PFS and OS
Data obtained from referred literature, dbEMT, 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. OS: overall survival; PFS: progression-free survival; CCA: cholangiocarcinoma; HCC: hepatocellular
carcinoma; IHCA: Inflammatory hepatocellular adenomas; ND: not described; TCGA: the cancer genome atlas; TCGA-LIHC: the cancer
genome atlas - liver hepatocellular carcinoma; TCGA-CHOL: the cancer genome atlas - cholangiocarcinoma

(p.Thr790Met), has been described in non-small-cell lung cancer, and prevents gefitinib- and erlotinib-
induced TKR inhibition [124,125] . Somatic mutations in ESR1, TYMS and EGFR genes related to drug resistance
[91]
have also been reported in PLC . A variant in an intron of VEGFC (g.177608775T>C) has been associated
with sorafenib efficacy in HCC patients. CC genotype of this mutation is accompanied by a decrease in PFS
and OS as compared with patients bearing CT or TT genotype . In iCCA, EGFR amplification has been
[116]
associated with the response to gefitinib (anti-EGFR therapy) .
[126]
Concerning BRAF, which is another major target of sorafenib, the missense mutation c.1799T>A (p.Val600Glu)
must be highlighted. This mutation has been found in many malignant tumors, such as melanoma, thyroid
cancer , colorectal cancer , but also HCC and iCCA . In patients with iCCA, OS was lower in those
[123]
[120]
[127]
[119]
with mutated BRAF (7.4% of cases) than in wild-type cases. The murine ortholog of this mutation in mouse
(c.1910T>A; p.Val637Glu), is a frequent feature in mouse liver cancer. In diethylnitrosamine-induced mouse
hepatocarcinogenesis, c.1910T>A mutation correlated with Erk1/Akt hyperphosphorylation, suggesting an
activation of MAPK and AKT pathways that results in stimulated cell proliferation [120,123] . Nevertheless, a
relationship between these mutations and the response to TKIs has not been well characterized.

DNA repair mechanisms (MOC-4)
Cancer cells can repair genome perturbations that are induced by antitumor-drugs through diverse
[113]
mechanisms that depend on the type of damage suffered by DNA . DNA repairing machinery includes
direct reversal of lesions by enzymes, such as O-6-methylguanine-DNA methyltransferase (MGMT),
nucleotide and base excision repair (NER and BER, respectively), DNA mismatch repair (MMR), homologous
recombination (HR) and non-homologous end joining (NHEJ). Deregulated expression and the appearance
of mutations in genes of the repair machinery have been observed in a variety of tumors. Since many cytotoxic
drugs used in the treatment of PLC act through alterations in DNA structure of cancer cells, MOC-4 play
an important role in the response of these tumors to chemotherapy. Table 6 provides a summary of both
germline and somatic mutations affecting DNA repair genes in HCC and CCA.

Germline pharmacogenetics
NER is the most important pathway involved in the elimination of bulky adducts induced by UV irradiation
and alkylating agents, such as platinum derivatives. More than 25 polypeptides participate in NER .
[128]
Germline variants in NER elements have been found in several cancers and some studies have related these
alterations to the lack of response to platinum-based chemotherapy [129,130] . However, mutations in these genes
are rarely found in HCC.

BER pathway also plays an essential role in DNA damage repair induced by alkylating agents and irradiation.
APE1 is an endonuclease involved in this process that recognizes and cleaves abasic (apurinic/apyrimidinic)
sites, where XRCC1 forms a complex with a DNA ligase to repair the gaps that have resulted from base
excision. In HCC patients, two genetic polymorphisms in XRCC1 (c.580C>T; p.Arg194Trp) and APE1
(c.444T>G; p.Asp148Glu) have been associated with resistance to cisplatin .
[131]