Identifying patients prior to treatment who are more likely to benefit from chemotherapeutic agents or more likely to experience adverse events is an aim of
personalized medicine. Pharmacogenomics offers a potential means of achieving this goal through the discovery of predictive germline genetic
biomarkers. When applied particularly to the treatment of head and
neck cancers, such information could offer significant benefit to patients as a means of potentially reducing morbidity associated with
platinum-based
chemotherapy. We developed a genome-wide, cell-based approach to identify single nucleotide polymorphisms (SNPs) associated with
platinum susceptibility and then evaluated these SNPs as predictors for response and toxicity in
head and neck cancer patients treated with
platinum-based
therapy as part of a phase II clinical trial. Sixty
head and neck cancer patients were evaluated. Of 45 genome-wide SNPs examined, we found that 2 SNPs, rs6870861 (P=0.004; false discovery rate [FDR] <0.05) and rs2551038 (P=0.005; FDR <0.05), were associated significantly with overall response to
carboplatin-based
induction chemotherapy when incorporated into a model along with total
carboplatin exposure. Interestingly, these 2 SNPs are associated strongly with the baseline expression of >20 genes (all P ≤10(-4)), and that 2 genes (SLC22A5 and SLCO4C1) are important organic
cation/
anion transporters known to affect
platinum uptake and clearance. Several other SNPs were associated nominally with
carboplatin-related hematologic toxicities. These findings demonstrate importantly that a genome-wide, cell-based model can identify novel germline genetic
biomarkers of
platinum susceptibility, which are replicable in a clinical setting with treated
cancer patients and seem clinically meaningful for potentially enabling future personalization of care in such patients.