title: Germline polymorphisms discovered via a cell-based, genome-wide approach predict platinum response in head and neck cancers.
abstract: 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.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Ziliak
authors.forename: Peter H
authors.initials: PH
authors.lastname: O'Donnell
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Im
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Peixian
authors.initials: P
authors.lastname: Chen
authors.forename: Shannon
authors.initials: S
authors.lastname: Delaney
authors.forename: Sunita
authors.initials: S
authors.lastname: Shukla
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.forename: R Stephanie
authors.initials: RS
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D016190:Carboplatin / Q000627:therapeutic use; D002460:Cell Line; D055106:Genome-Wide Association Study; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008954:Models, Biological; D010984:Platinum / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D010984:Platinum; D016190:Carboplatin