Figl Adina, Scherer Dominique, Nagore Eduardo, Bermejo Justo Lorenzo, Dickes Elke, Thirumaran Ranjit K, Gast Andreas, Hemminki Kari, Kumar Rajiv, Schadendorf Dirk
Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany.
Mutat Res. 2009 Feb 10;661(1-2):78-84. doi: 10.1016/j.mrfmmm.2008.11.011. Epub 2008 Nov 27.
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, N0, M0) 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.
单核苷酸多态性除了影响易感性外，还可能改变黑色素瘤患者的病程和生存期。在本研究中，我们评估了碱基切除修复基因XRCC1和APEX1中的多态性与皮肤黑色素瘤患者的总生存期（OS）、无转移生存期（MFS）以及首次转移后的生存期（SFM）之间的关联。我们采用等位基因鉴别法对400名德国黑色素瘤患者（Tx，N0，M0）的APEX1基因D148E、XRCC1基因-77 T>C、R280H和R399Q多态性进行了基因分型。将结果与患者的随访参数进行关联分析。我们还在529名西班牙黑色素瘤患者中评估了R399Q XRCC1多态性与MFS之间的显著关联。在Kaplan-Meier生存模型中，该多态性的AA基因型患者的中位OS为24.4年，而其他两种基因型为11.5年。同样，AA基因型患者的中位MFS为20.9年，其他两种基因型为5.3年。在多变量Cox比例风险模型中，对于400名德国黑色素瘤患者，AA基因型与MFS的风险比（HR）为0.40，95%可信区间（CI）为0.21 - 0.78，p = 0.007；与OS的风险比为0.32（95% CI 0.11 - 0.90，p = 0.03）。纳入529名西班牙黑色素瘤患者后，转移风险降低得到证实，合并后的HR为0.40（95% CI 0.24 - 0.68，p = 0.0006）。还发现XRCC1基因-77 T>C与SFM存在显著关联（HR 1.73，95% CI 1.02 - 2.94，p = 0.04）。我们的结果表明，非同义变异或位于DNA修复基因潜在调控区域的变异可能影响黑色素瘤患者的疾病转归，对患者监测和个体化治疗可能具有重要意义。
