Frequent genomic alterations in epithelium measured by microsatellite instabihty following allogeneic hematopoietic cell transplantation in humans
Frequent genomic alterations in epithelium measured by microsatellite instabihty following allogeneic hematopoietic cell transplantation in humans
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DOI：
10.1182/blood-2005-08-3431
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发表时间：
2006-04-15
期刊：
影响因子：
20.3
通讯作者：
Spyridonidis, A
中科院分区：
文献类型：
--
作者：
Faber, P;Fisch, P;Spyridonidis, A
虽然通常在癌症中发现，但在慢性炎症组织中也发现了微卫星的移码突变。同种异体造血细胞移植（HCT）可能通过移植物抗宿主反应产生慢性组织应激。我们检查了人类同种异体HCT后1至5061天获得的非肿瘤性上皮组织（结肠、颊），在3个四核苷酸和3个单核苷酸微卫星位点上存在基因组改变。在接受同种异体移植的75%和42%的患者中，分别在激光显微解剖的结肠隐窝和颊片中检测到表明四核苷酸重复的微卫星不稳定性（MSI）的新波段。相比之下，在对照组和强化化疗后患者的类似组织或自体HCT后患者的颊细胞中未发现MSI。在结肠中发现的MSI，经常受到移植物抗宿主病的影响，不是由于DNA修复蛋白的表达缺失或亚硝基化。临床完整口腔黏膜的MSI多见于HCT后较晚的时间点。在3例移植后鳞状细胞癌中也发现了MSI。我们的数据显示，同种异体HCT后，上皮细胞的基因组改变有规律地发生，并可能与移植后疾病的演变有关，包括继发性癌症。
Although typically found in cancers, frameshift mutations in microsatellites have also been detected in chronically inflamed tissues. Allogeneic hematopoletic cell transplantation (HCT) may potentially produce chronic tissue stress through graft-versus-host reactions. We examined non-neoplastic epithelial tissues (colon, buccal) obtained 1 to 5061 days after human allogeneic HCT for the presence of genomic alterations at 3 tetranucleotide and 3 mononucleotide microsatellite loci. Novel bands indicative of microsatellite instability (MSI) at tetranucleotide repeats were detected in laser-microdissected colonic crypts and in buccal smears of 75% and 42% of patients who received an allograft, respectively. In contrast, no MSI was found in similar tissues from control subjects and from patients after intensive chemotherapy or in buccal cells from patients after autologous HCT. The MSI found in colon, which was often affected by graft-versus-host disease, was not due to loss of expression or nitrosylation of DNA repair proteins. MSI in clinically intact oral mucosa was more frequently found at later time points after HCT. MSI was also found in 3 posttransplant squamous cell cancers examined. Our data show that genomic alterations in epithelium regularly occur after allogeneic HCT and may be implicated in the evolution of posttransplantation diseases, including secondary cancer.