Genetic deficiency of complement isoforms C4A or C4B predicts improved survival of metastatic renal cell carcinoma.
Genetic deficiency of complement isoforms C4A or C4B predicts improved survival of metastatic renal cell carcinoma.
复制标题
补体亚型 C4A 或 C4B 的遗传缺陷预示着转移性肾细胞癌的生存率提高。
DOI：
10.1016/j.juro.2008.11.013
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
Ellerhorst,JulieA
中科院分区：
文献类型：
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作者：
Zafar,GhazalI;Grimm,ElizabethA;Wei,Wei;Johnson,MarcellaM;Ellerhorst,JulieA
目的转移性肾细胞癌患者免疫治疗过程中的自身免疫现象与预后良好相关。我们已经报道了携带自身免疫相关HLA II类单倍型的IV期肾细胞癌患者的生存率提高。我们认为临床益处是由与这些单倍型相关的其他自身免疫相关基因的产物介导的。候选基因是互补的c4，它作为RCCX模块的一部分进行复制，可以存在于多个拷贝中，并以c4a&c4生物形态存在。这两种异构体的缺乏都与自身免疫有关。在目前的研究中，我们验证了c4aorc4b缺乏预测RCC患者生存率提高的假设。材料与方法采用rp1和tnxa / rp2同时扩增的方法测定RCCX总拷贝数。通过shai限制性片段长度多态性对c4a&c4balleles进行了区分。结果61例患者均检测到遗传复型。携带c4同型异构体的个体存活时间更长。c4aorc4b单拷贝患者诊断为转移性疾病后的中位生存期为7.75年，而对照组为1.25年（p = 0.001）。这与自身免疫II类基因型的获益无关。结论细胞因子治疗合并c4aor4b缺乏和肾细胞癌伴行手术或不手术均可提高生存率。这些数据支持我们的假设，即具有自身免疫基因型的肾细胞癌患者具有良好的预后，这是由针对肿瘤的自身免疫机制导致的。
PurposeAutoimmune phenomena during immunotherapy are associated with favorable outcomes in patients with metastatic renal cell carcinoma. We have reported improved survival in patients with stage IV renal cell carcinoma who carry autoimmunity associated HLA class II haplotypes. We propose that the clinical benefit is mediated by products of other autoimmunity associated genes linked to these haplotypes. A candidate gene is complementC4, which replicates as part of the RCCX module, can be present in multiple copies and exists asC4AandC4Bisoforms. Deficiencies of either isoform are associated with autoimmunity. In the current study we tested the hypothesis thatC4AorC4Bdeficiency predicts improved survival of patients with RCC.Materials and MethodsThe totalC4copy number was determined by simultaneous amplification ofRP1andTNXA/RP2to quantitate RCCX modules.C4AandC4Balleles were distinguished byPshAI restriction fragment length polymorphism.ResultsGenetic complotypes were determined in 61 patients. Individuals with a solitary copy of eitherC4isoform experienced longer survival. Median survival from the diagnosis of metastatic disease in patients with a solitary copy ofC4AorC4Bwas 7.75 years vs 1.25 in the comparison group (p = 0.001). This was independent of the benefit derived from autoimmune class II genotypes.ConclusionsImproved survival is seen in patients withC4AorC4Bdeficiency and renal cell carcinoma treated with cytokine therapy with or without surgery. These data support our hypothesis that patients with renal cell carcinoma who have autoimmune genotypes have favorable outcomes resulting from autoimmune mechanisms directed to the tumor.