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Kaehler et al. Cancer Drug Resist 2019;2:18-30 I http://dx.doi.org/10.20517/cdr.2019.05 Page 25
[84]
posttranscriptional regulation via the 3’-UTR . Nevertheless, no significant association of 421C>A was
found or results were contradictory. Besides these two SNPs, 376C>T leads to formation of a premature stop
codon (Q126stop, rs72552713) resulting in diminished protein expression and could be associated to drug
[85]
hypersensitivity . Conversely, the promoter SNP -15994C>T results in increased BCRP expression and
[86]
imatinib clearance .
The ABCC subfamily and their genetic variants in chemoresistance
For the ABCC subfamily, twelve members have been described yet. With regards to chemoresistance ABCC1,
ABCC2 and ABCC3 have been intensively investigated. While anticancer drugs of the new generation are
mainly transported by ABCB1 and ABCG2, several cytostatics, e.g., vincristine or cisplatin, are substrates
[87]
for these transporters [Table 1] . As distinct clinical studies on association of ABCC1 and ABCC3 to drug
resistance are lacking, most data is present on ABCC2. Most prominent SNPs are -24C>T in the ABCC2
[68]
promoter region (rs7177620) being associated to reduced expression and activity of the protein . This could
[88]
thus be linked to higher methotrexate plasma levels . Together with 1249G and 3972T, -24T haplotype
[89]
was associated with imatinib resistance . Regarding therapy using platinum or platinum-derivates, e.g.,
carboplatin, it was observed that 4544G>A (rs8187710) correlated with adverse survival rates of patients
[90]
suffering from non-small cell lung cancer . Furthermore, this SNP was associated with doxorubicin-
[59]
induced cardiotoxicity requiring closer monitoring during treatment .
Chemoresistance, epigenetics and miRNA regulation
It is well known that protein expression can be modulated on the transcriptional level by epigenetics, as
well as post-transcriptionally by microRNAs or RNA-binding proteins. Analyses of epigenetics, e.g., DNA
methylation or histone modification, remain inconclusive for ADME genes so far. In several studies, data on
promoter methylation of the efflux transporters ABCB1 or ABCG2 showed contrary differential methylation
in various types of cancer [91-96] . In addition, hereditary variants in promoter regions might directly impair
binding of transcription factors leading to differential gene expression. This has also been shown for several
cytochrome P450 enzymes pointing to gene expression regulation by methylation, e.g., CYP1A2, CYP2C19
and CYP2D6 [97,98] .

Main research has been performed for transcriptional control by microRNAs resulting in blockade of
[99]
translation or degradation of their respective target mRNAs . This interaction can be impaired by
hereditary variants of the mRNA 3’-UTRs in target genes. For ABC-transporters, several microRNA
interactions have been described so far, e.g., miR-508-3p/ABCB1, miR-212/ABCG2 or miR-379/ABCC2 [91,100,101] .
For the latter, it was observed that ABCC2 -24C>T, 1249G>A and 3972C>T variant haplotypes led to
pronounced microRNA-dependent suppression compared to wild-types [102] .

Interestingly, the interaction of microRNA/mRNA can also be impaired by selective expression of
alternative mRNA 3’-UTRs by the cancer cell. As these shorter 3’-UTRs lack the microRNA-binding regions,
regulation of respective microRNA can be abolished. This phenomenon was observed not only for ABCG2
in mitoxantrone-resistant colon cancer cells, but also for ABCB1 in chronic myeloid leukemia cells [103,104] .
Potentially, this is also relevant for other ABC transporters or biotransforming enzymes (reviewed in [105,106] ).
Further studies are required to investigate this mechanism and its regulation.

Within the last decade it was observed that microRNA expression pattern are distinct for each tumor and
can be altered during in treatment with anticancer drugs (reviewed in [107] ). Thus, haplotype-dependent
microRNA interaction and regulation of mRNA expression might contribute to differential susceptibility of
tumors and patients.

CONClUsIONs aND OUTlOOK
Pharmacogenetic testing of somatic and germline mutations is an emerging field in oncology. Presence of
hereditary variants are relevant for avoidance of adverse drug events in some classic chemotherapy regimen,