Candidate pathway-based genetic association study of platinum and platinum–taxane related toxicity in a cohort of primary lung cancer patients

Highlights

• Cohort of 950 primary lung cancer patients treated with a platinum drug

• DNA and clinical data available for all patients

• 40% developed peripheral neuropathy.

• Diabetes and drug dose increased risk of neuropathy.

• SNPs associated with glutathione metabolism and DNA repair associated with neuropathy

Abstract

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity secondary to chemotherapy. Genetic factors may be important in predisposing patients to this adverse effect.

Patients and methods

We studied 950 primary lung cancer patients, who received platinum or platinum-combination drug chemotherapy and who had DNA available for study. We analyzed epidemiological risk factors in 279 CIPN patients and 456 non-CIPN patients and genetic risk factors in 141 CIPN patients and 259 non-CIPN patients. The risk factors studied included demographic, diagnostic, and treatment data, as well as 174 tag SNPs (single nucleotide polymorphisms) across 43 candidate genes in the glutathione, cell cycle, DNA repair, cell signaling, and apoptosis pathways.

Results

Patients who had diabetes mellitus were more likely to have CIPN (p = 0.0002). Other epidemiologic risk factors associated with CIPN included number of cycles (p = 0.0004) and type of concurrent chemotherapy (p < 0.001). SNPs most associated with CIPN were in glutathione peroxidase 7 (GPX7) gene (p values 0.0015 and 0.0028, unadjusted and adjusted) and in ATP-binding cassette sub-family C member 4 (ABCC4) gene (p values 0.037 and 0.006, unadjusted and adjusted). We also found other suggestive associations in methyl-o-guanine-methyl-transferase (MGMT) and glutathione-S-transferase (GST) isoforms.

Conclusions

Epidemiological and genetic risk factors associated with CIPN in this cohort, included the type of chemotherapy drug, intensity of chemotherapy treatment, and genes known to be associated with chemotherapy resistance. These findings suggest that differentiating between cytotoxic and neurotoxic mechanisms of chemotherapy drugs is challenging but represents an important step toward individualized therapy and improving quality of life for patients.

Introduction

Combination chemotherapy with a platinum drug or a platinum drug combined with a taxane is used for many types of cancer including ovarian, testicular, lung, breast, and colorectal [1], [2]. Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with this treatment [3]. It is typically a sensory neuropathy that may necessitate dose reduction and lead to impaired quality of life [3], [4], [5]. Treatment and preventive strategies have had limited success [6], [7], [8], [9], [10]. CIPN is the major dose limiting toxicity for this common chemotherapy regime. The mechanism underlying neurotoxicity is not understood. Apoptosis of primary sensory dorsal root ganglion (DRG) neurons due to formation of platinum adducts in nuclear and mitochondrial DNA is a central mechanism in rodent models [11], [12], [13], [14], [15], [16], [17], [18], [19]. This results in mitochondrial dysfunction and disruption in cell cycle [14], [15], [19]. Thus the mechanisms of neurotoxicity and cancer cytotoxicity have many similarities and separating the beneficial cytotoxic effect from the neurotoxic effect may be difficult.

A different approach to preventing neurotoxicity may result from understanding why some patients develop CIPN, while others do not. This can be approached from an epidemiological and genetic perspective. A large study using Medicare insurance records identified that the number of cycles of chemotherapy, patient age and cumulative drug dose, were associated with the risk of developing CIPN [2], [20], [21], [22]. Genetic risk factors have been associated with polymorphisms in glutathione-S-transferase (GST) gene family isoforms [2], [20], [21], [22], especially GSTP-1 [2], [20], [21], [22] signaling pathways, metal transporters, growth factors, and DNA repair genes [2], [11], [23], [24], [25], [26], [27].

We now report both an epidemiological and multi-gene association study in a cohort of 950 primary lung cancer patients who received platinum and platinum–taxane chemotherapy. Medical records were available for identifying demographic and epidemiologic data for all of these patients. DNA samples were available for the genetic study. We used a candidate pathway-based approach because it is a hypothesis driven approach to the use of single nucleotide polymorphism data. This contrasts with genome-wide association studies (GWAS) that may identify polymorphisms in genes not mechanistically known to be associated with metabolism of the specific drug but also identify many more false-positive associations. The genes and pathways chosen were based on their known involvement with metabolism that focuses on glutathione, cell cycle, cell signaling, apoptosis, and DNA repair pathways, all of which have been implicated in animal model studies of CIPN [2], [11], [23], [24], [25], [26], [27].