Page 49 - Read Online

Crisafulli et al. Cancer Drug Resist 2019;2:225-41 I http://dx.doi.org/10.20517/cdr.2018.008 Page 227

Table 1. Discovery strategies for novel pharmacogenetic and pharmacogenomic traits
Advantages Disadvantages
Candidate Polymorphism Analysis
1. Rapid execution of the assay 1. Polymorphisms need to have strong effects toward the phenotype
2. Focus on genes likely involved in treatment response and toxicity 2. It is based on validated knowledge, ad may miss potentially-involved
unknown genes
3. It ignores de-novo mutations in target genes
Pathway analysis
1. Focus on pathways, downstream the gene(s) of interest, that are 1. It may miss potentially involved, but still unidentified, signaling
highly likely to be involved in the drug action cascades
2. It highlights whole signaling cascades, for higher sensitivity for genes 2. Data analysis is complex given the interplay of multiple interacting
with smaller phenotypic effects genes
3. It can identify new polymorphisms or new genes within a given 3. It requires investigating large sample case-series
pathway
4. More likely to explain inter-individual variation in drug response
“Whole genome strategies”
1. They provide a complete gene- or protein- expression profile (tumor 1. The lack of hypothesis-driven analyses may increase the risk of false
or individual) positives
2. They provide information on novel associations 2. Complex data management and analysis procedures are required
3. They generate large amounts of data 3. Costs and complexity still high for the clinics
4. Useful in predicting tumor response

Cancer-driving somatic DNA mutations and inherited DNA variants that may impact on
pharmacogenetic and pharmacogenomic strategies
Cancer-causing DNA alterations, such as somatic DNA mutations and inherited DNA variants, are not
a direct focus of pharmacogenetic and pharmacogenomic studies. However, mutated cancer drivers are
becoming more and more actionable targets for therapy. They can also affect key metabolic pathways
that may modify drug pharmacokinetics and pharmacodynamics. As such, they can play a key role in
pharmacogenetic and pharmacogenomic discovery.

Key examples are DNA-damage response pathways (ATM, CHEK2, BRIP1, BRCA1, BRCA2, PALB2),
[27]
which are associated with an increase in breast cancer risk . In particular, germline pathogenic variants
in BARD1, BRCA1, BRCA2, PALB2 and RAD51D are associated with high risk (odds ratio > 5.0) for triple-
negative breast cancer (TNBC) [28,29] . BRCA1, BRCA2, PALB2 variants are also associated with increased risk
[30]
of ovarian and other cancers [31,32] . Pathogenic variants in BRIP1, RAD51C and TP53 are associated with
[33]
moderate risk (odds ratio > 2) for TNBC, whereby hereditary pathogenic variants are detected in 12.0% of
TNBC .
[28]
Corresponding mutations in the BRCA1, BRCA2, PALB2 genes are detected in a fraction of sporadic breast
[34]
and ovarian cancer . Notably, mutations in BRCA1, BRCA2 are associated to better therapeutic response
[35]
to PARP inhibitors , making such mutations effective tools for therapy choice. Other, cancer-associated
somatic mutations, e.g., the mutations at codons 12 or 13 in the Ki-RAS gene, predict lack of response to
[36]
EGFR-targeted therapy in colon cancer . Mutations in the EGFR kinase ATP-binding pocket mandate
[37]
choosing specific tyrosine kinase inhibitors . Of interest, such EGFR mutants also are predictors of
[38]
response to unrelated therapy .
It should be noted that mutated cancer-driving genes may play a key role as metabolic-pathway modifiers.
Examples are mutations in TP53, which differentially impact on metabolic pathways and apoptotic
responses, thus modifying the impact of anticancer chemotherapy. Not surprisingly, TP53 mutations are
[39]
predictive of poor response to therapy . Activation of transcription of c-Myc impacts on main metabolic
[40]
pathways, on ribosomal biogenesis, and on lipid metabolism . In vivo efficacy of the Bcl-2 antagonist ABT-
[41]
737 depends on c-Myc activation . Furthermore, c-myc/p53 interactions determine sensitivity of colon