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

Cassandra Johnson, Vernon S. Pankratz, Ana I. Velazquez, Jeremiah A. Aakre, Charles Lawrence Loprinzi, Nathan P Staff, Anthony John Windebank, Ping Yang

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)124-128
Number of pages5
JournalJournal of the Neurological Sciences
Volume349
Issue number1-2
DOIs
StatePublished - Feb 15 2015

Fingerprint

Genetic Association Studies
Platinum
Lung Neoplasms
Peripheral Nervous System Diseases
Drug Therapy
taxane
Genes
Single Nucleotide Polymorphism
Epidemiologic Factors
Guanine
Glutathione Peroxidase
Transferases
Combination Drug Therapy
Glutathione Transferase
DNA Repair
Pharmaceutical Preparations
Glutathione
Diabetes Mellitus
Cell Cycle
Protein Isoforms

Keywords

  • Chemotherapy induced peripheral neuropathy
  • Diabetes
  • Genetic
  • Paclitaxel
  • Platinum drugs
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Candidate pathway-based genetic association study of platinum and platinum-taxane related toxicity in a cohort of primary lung cancer patients. / Johnson, Cassandra; Pankratz, Vernon S.; Velazquez, Ana I.; Aakre, Jeremiah A.; Loprinzi, Charles Lawrence; Staff, Nathan P; Windebank, Anthony John; Yang, Ping.

In: Journal of the Neurological Sciences, Vol. 349, No. 1-2, 15.02.2015, p. 124-128.

Research output: Contribution to journalArticle

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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.",
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author = "Cassandra Johnson and Pankratz, {Vernon S.} and Velazquez, {Ana I.} and Aakre, {Jeremiah A.} and Loprinzi, {Charles Lawrence} and Staff, {Nathan P} and Windebank, {Anthony John} and Ping Yang",
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T1 - Candidate pathway-based genetic association study of platinum and platinum-taxane related toxicity in a cohort of primary lung cancer patients

AU - Johnson, Cassandra

AU - Pankratz, Vernon S.

AU - Velazquez, Ana I.

AU - Aakre, Jeremiah A.

AU - Loprinzi, Charles Lawrence

AU - Staff, Nathan P

AU - Windebank, Anthony John

AU - Yang, Ping

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N2 - 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.

AB - 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.

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KW - Diabetes

KW - Genetic

KW - Paclitaxel

KW - Platinum drugs

KW - Single nucleotide polymorphism

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