DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy.

Abstract

INTRODUCTION:

Genetic polymorphisms that affect DNA repair capacity can modulate the efficacy and toxicity of cytotoxic agents. Therefore, the aim of our study was to evaluate the influence of genetic variability in DNA repair genes on treatment outcome in patients with malignant mesothelioma (MM) treated with gemcitabine-platinum combination chemotherapy.

METHODS:

In total, 109 patients with MM were genotyped for 10 polymorphisms in XRCC1, NBN, RAD51, and XRCC3 genes. The influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity was determined by logistic regression analysis, whereas their influence on survival was estimated by Cox proportional hazards model.

RESULTS:

There were no associations between the investigated polymorphisms and tumor response, but we observed a significant association between XRCC1 399Gln allele and reduced overall survival (hazards ratio = 1.70; 95% confidence interval [CI] 1.06-2.73; p = 0.028). Interaction between XRCC1 399Gln allele and C-reactive protein levels revealed that carriers of at least one XRCC1 399Gln allele with C-reactive protein levels above median had significantly shorter overall survival time compared with other patients (12.9 months versus 25.3 months, log-rank p < 0.001). We also observed an association between XRCC1 399Gln and lower frequency of leukopenia (odds ratio [OR] = 0.25; 95% CI 0.09-0.67; p = 0.006), neutropenia (OR = 0.24; 95% CI 0.09-0.68; p = 0.007), and thrombocytopenia (OR = 0.27; 95% CI 0.09-0.84; p = 0.024). In addition, NBN 3474A>C, XRCC3 -316A>G, and Thr241Met polymorphisms showed significant associations with treatment-related toxicity.

CONCLUSIONS:

Our results support the hypothesis that DNA repair gene polymorphisms, particularly XRCC1 Arg399Gln, may modify the response to gemcitabine-platinum combination chemotherapy and, for the first time, show this effect in patients with MM.

• Authors: Nina Erčulj, Viljem Kovač, Julija Hmeljak, Alenka Franko, Metoda Dodič-Fikfak, Vita Dolžan
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 7 Issue 10 Pg. 1609-17 (Oct 2012) ISSN: 1556-1380 [Electronic] United States
• PMID: 22982660 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA-Binding Proteins
• NBN protein, human
• Nuclear Proteins
• X-ray Repair Cross Complementing Protein 1
• X-ray repair cross complementing protein 3
• XRCC1 protein, human
• Deoxycytidine
• Platinum
• DNA
• RAD51 protein, human
• Rad51 Recombinase
• Gemcitabine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Case-Control Studies
• Cell Cycle Proteins (genetics)
• DNA (analysis, genetics)
• DNA Repair (genetics)
• DNA-Binding Proteins (genetics)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Female
• Follow-Up Studies
• Humans
• Male
• Mesothelioma (drug therapy, genetics, mortality)
• Middle Aged
• Neoplasm Staging
• Nuclear Proteins (genetics)
• Peritoneal Neoplasms (drug therapy, genetics, mortality)
• Platinum (administration & dosage)
• Pleural Effusion, Malignant (drug therapy, genetics, mortality)
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide (genetics)
• Prognosis
• Rad51 Recombinase (genetics)
• Survival Rate
• X-ray Repair Cross Complementing Protein 1
• Gemcitabine