RGD Reference Report - DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy. - Rat Genome Database

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

Authors: Erčulj, Nina  Kovač, Viljem  Hmeljak, Julija  Franko, Alenka  Dodič-Fikfak, Metoda  Dolžan, Vita 
Citation: Erčulj N, etal., J Thorac Oncol. 2012 Oct;7(10):1609-17. doi: 10.1097/JTO.0b013e3182653d31.
RGD ID: 151347428
Pubmed: PMID:22982660   (View Abstract at PubMed)
DOI: DOI:10.1097/JTO.0b013e3182653d31   (Journal Full-text)


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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
XRCC1Humanmalignant mesothelioma treatmentIAGP  RGD 
Xrcc1Ratmalignant mesothelioma treatmentISOXRCC1 (Homo sapiens) RGD 
Xrcc1Mousemalignant mesothelioma treatmentISOXRCC1 (Homo sapiens) RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
XRCC1HumanLeukopenia susceptibilityIAGP DNA:missense mutation:cds: p.R399Q (human)RGD 
XRCC1HumanNeutropenia susceptibilityIAGP DNA:missense mutations:cds: p.R399Q (human)RGD 
XRCC1HumanThrombocytopenia susceptibilityIAGP DNA:missense mutations:cds: p.R399Q (human)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Xrcc1  (X-ray repair cross complementing 1)

Genes (Mus musculus)
Xrcc1  (X-ray repair complementing defective repair in Chinese hamster cells 1)

Genes (Homo sapiens)
XRCC1  (X-ray repair cross complementing 1)


Additional Information