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 the aim of personalized medicine. Pharmacogenomics offers a potential means of achieving this 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 two SNPs, rs6870861 (p=0.004; false discovery rate [FDR] <0.05) and rs2551038 (p=0.005; FDR <0.05), were significantly associated with overall response to carboplatin-based induction chemotherapy when incorporated into a model along with total carboplatin exposure. Interestingly, these two SNPs are strongly associated with the baseline expression of ≥20 genes (all p≤10 −4 ) and two of the genes (SLC22A5 and SLCO4C1) are important organic cation/anion transporters known to affect platinum uptake and clearance. Several other SNPs were nominally associated with carboplatin-related hematologic toxicities. These findings importantly demonstrate that a genomewide cell-based model can identify novel germline genetic biomarkers of platinum susceptibility © 2011 Mosby, Inc. All rights reserved. * Address for correspondence and reprints: R. Stephanie Huang, 900 E 57 th Street, KCBD room 7148, The University of Chicago, Chicago, IL 60637. Phone: (773) 702-9363; Fax: (773) 702-0963; rhuang@medicine.bsd.uchicago.edu. § these authors contributed equally to the work Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The authors have no potential conflicts of interest to declare. The authors did not use editorial support for preparation of the manuscript. NIH Public Access

Clinical Evaluation of Cisplatin Sensitivity of Germline Polymorphisms in Neoadjuvant Chemotherapy for Urothelial Cancer

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