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.

Trial registration: ClinicalTrials.gov NCT01172470.

Conflict of interest statement

The authors have no potential conflicts of interest to declare. The authors did not use editorial support for preparation of the manuscript.

Copyright © 2011 Mosby, Inc. All rights reserved.

Figures

Figure 1. Flow chart of SNP discovery and validation methods used

Pathway 1: The Triangle approach was used as described previously , which resulted in a list of SNPs associated with carboplatin sensitivity (p≤10−4) and also with baseline gene expression in these cell lines (p<3.8×10−6) and the gene expression of the “target gene” correlated back to carboplatin sensitivity (p<0.05). Pathway 2: Genome-wide association was performed on the “platinum sensitivity-enriched” ASN population (p<10−4) and the top ASN SNPs were replicated in a multi-ethnic population consisting of CEU and YRI samples (p<0.05) as described previously . SNPs from Pathways 1 and 2 were then combined and interrogated against clinically relevant phenotypes from a head and neck cancer phase II clinical trial involving carboplatin induction therapy. International HapMap lymphoblastoid cell lines (LCLs): CEU/CEPH are LCLs from Utah residents with northern and western European ancestry; YRI are LCLs from Yoruba people of Ibadan, Nigeria; ASN are LCLs from Asian individuals (Chinese in Beijing and Japanese in Tokyo). SNP = single nucleotide polymorphism.

Figure 2. Delivered carboplatin dose correlates strongly with tumor response in head and neck cancer patients

Linear regression analysis was performed between carboplatin exposure and response to drug in 52 head and neck cancer patients from the UC 12019 trial. The y-axis depicts overall response post-carboplatin treatment categorized into 4 groups; each was given a nominal value: 1 stands for complete response, 2 for partial response, 3 for stable disease and 4 for progressive disease. The x-axis, carboplatin exposure, was calculated by multiplying the desired carboplatin dose by the number of cycles of platinum given, divided by the time over which the drug was given. The negative correlation between carboplatin exposure and the four overall response categories suggests that the higher the carboplatin exposure, the better the response.

Figure 3. rs2551038 genotype is significantly associated with carboplatin sensitivity in vitro and in vivo

A) Genotype and carboplatin sensitivity (depicted by % cellular survival after 80 µM carboplatin treatment) association in HapMap CEU samples. B) genotype and carboplatin sensitivity (depicted by tumor response post-carboplatin-containing induction therapy) association in UC12019 head and neck cancer patients. Overall response in 3B was categorized into 4 groups and each was given a nominal value: 1 stands for complete response, 2 for partial response, 3 for stable disease and 4 for progressive disease.