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Page 54 Olivera et al. Cancer Drug Resist 2019;2:53-68 I http://dx.doi.org/10.20517/cdr.2018.25
[1,2]
single nucleotide polymorphisms (SNPs), accounting for approximately 90% of human genome variability .
However, key variants influencing PGx include also genomic insertions, deletions and repeats, and genetic
copy number variations, in addition to SNP. The aim of this review is to provide an easy-to-interpret
summary of the drug-germline polymorphisms pairs (mainly SNPs) that currently can be used to help in
oncologists in the therapeutic decision making.

PGx is related with pharmacology and thus, the molecular knowledge of drugs’ transporters, metabolizers
[1]
and mechanism of action are required . Adverse drug reactions (ADRs) as well as drug efficacy are
associated with particular genetic variants of each individual, related to the genes coding for all the
components interacting with the drug inside the patients’ body. For this reason, clinical practice must turn
[2-4]
into personalized and precision medicine . However, how to implement PGx in the daily routine is not free
of difficulties and physicians do need the support of rigorous and evidence-based information. The axis of
this work consists in a review of the available associations and guidelines of drug/germline polymorphisms,
with the highest evidence level, that could be applied within the clinical practice in pediatric and adult
oncologic patients. Tumor (somatic) genetic variants are out of the scope of this review. The aim is providing
clinicians with a helpful tool for therapeutic prescribing, regarding the individual patient, which can be
useful even before having tumor tissue analyses available.

[3]
Most of the existing PGx information is compiled in PharmGKB , a free access database created, curated
and managed by the University of Stanford and funded by US National Institutes of Health (NIH/NIGMS).
PharmGKB data are under a Creative Commons license. It counts with a group of experts working on the
dissemination of knowledge about the impact of human genetic variation on drug responses and on the
translation of PGx into clinical practice.

SOURCES OF INFORMATION
In www.pharmGKB.org website an extensive and constantly updated compilation of the PGx knowledge can
[3]
be found . It is mainly based on the results of the articles published worldwide, mainly included in PubMed
database. In our case, our focus is the subset of data that is ready to be used in the clinical practice, so our
references on this database will be the following:

PGx Prescribing Info: this part contains drug dosing guidelines that take into consideration patient
genotype, published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) , the Royal
[5]
Dutch Association for the Advancement of Pharmacy - Pharmacogenetics Working Group (DPWG,
manually curated by PharmGKB) , or other professional society (PRO, manually curated by PharmGKB) .
[6]
[7]
Drug Labels: Regulatory agencies as the US Food and Drug Administration (FDA) , the European
[8]
[10]
[9]
Medicines Agency (EMA) , the Pharmaceuticals and Medical Devices Agency (PMDA) from Japan and
[11]
Health Canada Santé Canada (HCSC) have included the recommendation of a genetic test prior to the
use of many drugs. The drug label indicates if the test is required, recommendable, actionable or simply
informative .
[3]
Clinical Annotations: drug/polymorphism relationships graded with a “Level of Evidence”. This scientific
evidence rank is assigned by the PharmGKB experts from1 to 4 (1A, 1B, 2A, 2B, 3 and 4), 1A being the
highest. In level 1A annotations, the variant-drug combination is included in a CPIC or a PGx guide
approved by the medical society or implemented in a PGRN (Pharmacogenomics Research Network) site
or in another important health system. In level 1B annotations, the preponderance of evidence shows an
association that replicates in more than one cohort with significant P-values, and preferably will have a
strong effect size. Level 2 includes variants with moderate evidence. Level 2A marks annotations for variant-