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Page 682 Alonso-Peña et al. Cancer Drug Resist 2019;2:680-709 I http://dx.doi.org/10.20517/cdr.2019.006

Figure 1. Scheme of mechanisms of chemoresistance (MOC): reduction in intracellular concentration of active drugs (MOC-1 and
MOC-2), changes in molecular targets (MOC-3), enhanced DNA repair mechanisms (MOC-4), altered balance between survival and
apoptosis pathways (MOC-5), tumor microenvironment (MOC-6) and epithelial-mesenchymal transition (MOC-7)

Figure 2. Top 20 most frequently mutated genes in A: hepatocellular carcinoma (HCC); and B: cholangiocarcinoma (CCA). Adapted from
COSMIC database (https://cancer.sanger.ac.uk/cosmic)

Given the complexity and heterogeneity of PLCs, the use of personalized diagnosis based on the analysis of
genetic variants is becoming an urgent need to establish an optimized treatment for each patient. Therefore,
the clinical relevance of pharmacogenetic studies is increasing. The mutational signature has identified
the main genes with the most relevant alterations both in HCC and CCA. This includes oncogenes and
tumor suppressor genes involved in signaling pathways related to survival, proliferation, differentiation
and DNA repair [Figure 2]. In this review, we have summarized current knowledge regarding mutations
identified in HCC and CCA, and their role in multidrug resistance (MDR) phenotype and patient outcome.
We have distinguished between somatic mutation, i.e., acquired by tumor cells during carcinogenesis, and
germline mutations, i.e., inherited genetic alterations. For the nomenclature of the mutations that appear in
this review, the updated recommendations of the Sequence Variant Description Working Group , which
[13]
operates under the auspices of three international organizations: the Human Genome Variation Society,
the Human Varioma Project and the Human Genome Organization (HUGO), have been followed. Single-
nucleotide polymorphisms (SNP) have been considered substitutions of a single nucleotide that occur within
a population with a frequency higher than 1%, whereas a single-nucleotide variant, without any limitations
of frequency, that may arise in cancer cells is called a single-nucleotide alteration (SNA).