Single nucleotide polymorphisms in DNA repair genes XRCC1 and APEX1 in progression and survival of primary cutaneous melanoma patients

被引:23
|
作者
Figl, Adina [1 ,2 ]
Scherer, Dominique [2 ]
Nagore, Eduardo [3 ]
Bermejo, Justo Lorenzo [2 ]
Dickes, Elke
Thirumaran, Ranjit K. [2 ]
Gast, Andreas [2 ]
Hemminki, Kari [2 ,4 ]
Kumar, Rajiv [2 ]
Schadendorf, Dirk [5 ]
机构
[1] Univ Hosp Mannheim, Skin Canc Unit, German Canc Res Ctr Heidelberg, Dept Dermatol, D-68167 Mannheim, Germany
[2] German Canc Res Ctr, Div Mol Genet Epidemiol, D-6900 Heidelberg, Germany
[3] Inst Valenciano Oncol, Dept Oncol, Valencia, Spain
[4] Karolinska Inst, Ctr Family Med, Huddinge, Sweden
[5] Univ Hosp, Dept Dermatol, Essen, Germany
关键词
Melanoma; Progression; Survival; Polymorphisms; XRCC1; APEX1; BASE EXCISION-REPAIR; CELL LUNG-CANCER; RISK; METASTASIS; ERCC2;
D O I
10.1016/j.mrfmmm.2008.11.011
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Single nucleotide polymorphisms, besides influencing susceptibility can potentially alter progression and survival in melanoma patients. In this study we evaluated the association of polymorphisms in the base-excision repair genes XRCC1 and APEX1 with overall survival (OS), metastasis-free survival (MFS) and survival following the first metastasis (SFM) in patients with cutaneous melanoma. We genotyped the D148E APEX1, -77 T > C XRCC1, R280H XRCC1, and R399Q XRCC1 polymorphisms in 400 German melanoma patients (Tx, NO, MO) using an allelic discrimination method. The results were correlated with the patient follow-up parameters. The significant association detected between the R399Q XRCC1 polymorphism and MFS was also evaluated in 529 Spanish melanoma patients. In a Kaplan-Meier survival model the AA genotype of the polymorphism showed a median OS of 24.4 years compared to 11.5 years for two other genotypes. Similarly patients with the AA genotype showed median MFS of 20.9 years compared to 5.3 years for two other genotypes. In a multivariate Cox proportional hazard model, the AA genotype was associated with a hazard ratio (HR) of 0.40, 95% (CI 0.21-0.78, p = 0.007) for MFS and 0.32 (95% CI 0.11-0.90, p = 0.03) for OS in 400 German melanoma patients. The decreased risk of metastasis was confirmed by adding 529 Spanish melanoma patients with a combined HR of 0.40 (95% CI 0.24-0.68, p = 0.0006). A significant association with SFM was also found for -77 T > C XRCC1 (HR 1.73, 95% CI 1.02-2.94, p = 0.04). Our results show that non-synonymous variants or those located in potential regulatory regions of DNA repair genes probably influence the disease outcome in melanoma patients and have potentially significant implications for patient surveillance and tailored treatment. (C) 2008 Elsevier B.V. All rights reserved.
引用
收藏
页码:78 / 84
页数:7
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