Polymorphisms in the CD28/CTLA4/ICOS genes: role in malignant melanoma susceptibility and prognosis?
Polymorphisms in the CD28/CTLA4/ICOS genes: role in malignant melanoma susceptibility and prognosis?
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DOI：
10.1007/s00262-009-0751-2
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Kumar R
中科院分区：
文献类型：
--
作者：
Bouwhuis MG;Gast A;Figl A;Eggermont AM;Hemminki K;Schadendorf D;Kumar R
黑色素瘤患者白癜风的出现和原发病变的自然消退说明了肿瘤免疫和自身免疫之间的关系。 T淋巴细胞在肿瘤免疫和自身免疫中发挥着重要作用。 CD28、细胞毒性 T 淋巴细胞抗原 4 (CTLA4) 和诱导共刺激分子 (ICOS) 分子是 T 淋巴细胞激活中重要的次级信号分子。据报道，CD28/CTLA4/ICOS 基因区域的单核苷酸多态性 (SNP) 与多种自身免疫性疾病相关，包括 1 型糖尿病、SLE、自身免疫性甲状腺疾病和乳糜泻。在这项研究中，我们研究了 CD28、CTLA4 和 ICOS 基因中的 SNP 与黑色素瘤风险的关联。我们还评估了不同多态性对黑色素瘤患者的预后影响。在由 763 名德国黑色素瘤患者和 734 名德国健康对照组成的队列中，对这三个基因的 24 个标记 SNP 和另外 4 个 SNP 进行了基因分型。在 587 例属于 I 期或 II 期的黑色素瘤病例中确定了对预后的影响。一般来说，黑色素瘤患者和对照组之间没有检测到基因型或等位基因频率的差异。然而，CD28 基因中两个多态性的变异等位基因在病例和对照中分布存在差异。同样，除了 CD28 基因中的 rs3181098 多态性之外，没有观察到任何多态性与预后的关联。此外，ICOS 基因中 rs11571323 多态性具有 AA 基因型的个体表现出总体生存率降低。然而，考虑到多重假设检验的校正，我们的结果表明，CD28、CTLA4 和 ICOS 基因的多态性至少不会调节黑色素瘤的风险，也不会影响研究人群的疾病预后。本文的在线版本 (doi:10.1007/s00262-009-0751-2) 包含补充材料，可供授权用户使用。
The appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and inducible costimulator (ICOS) molecules are important secondary signal molecules in the T lymphocyte activation. Single nucleotide polymorphisms (SNPs) in the CD28/CTLA4/ICOS gene region were reported to be associated with several autoimmune diseases including, type-1 diabetes, SLE, autoimmune thyroid diseases and celiac disease. In this study, we investigated the association of SNPs in the CD28, CTLA4 and ICOS genes with the risk of melanoma. We also assessed the prognostic effect of the different polymorphisms in melanoma patients. Twenty-four tagging SNPs across the three genes and four additional SNPs were genotyped in a cohort of 763 German melanoma patients and 734 healthy German controls. Influence on prognosis was determined in 587 melanoma cases belonging to stage I or II of the disease. In general, no differences in genotype or allele frequencies were detected between melanoma patients and controls. However, the variant alleles for two polymorphisms in the CD28 gene were differentially distributed in cases and controls. Similarly no association of any polymorphism with prognosis, except for the rs3181098 polymorphism in the CD28 gene, was observed. In addition, individuals with AA genotype for rs11571323 polymorphism in the ICOS gene showed reduced overall survival. However, keeping in view the correction for multiple hypothesis testing our results suggest that the polymorphisms in the CD28, CTLA4 and ICOS genes at least do not modulate risk of melanoma and nor do those influence the disease prognosis in the investigated population. The online version of this article (doi:10.1007/s00262-009-0751-2) contains supplementary material, which is available to authorized users.
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