Chromosome fragility in patients with Fanconi anaemia: diagnostic implications and clinical impact
Chromosome fragility in patients with Fanconi anaemia: diagnostic implications and clinical impact
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DOI：
10.1136/jmg.2010.084210
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发表时间：
2011-04-01
影响因子：
4
通讯作者：
Surralles, Jordi
中科院分区：
文献类型：
--
作者：
Castella, Maria;Pujol, Roser;Surralles, Jordi
背景范可尼贫血（FA）是一种罕见的综合征，其特征是骨髓衰竭、畸形和癌症倾向。由 DNA 链间交联 (ICL) 诱导剂（例如二环氧丁烷 (DEB) 或丝裂霉素 C (MMC)）诱导的染色体脆性是诊断 FA 的“金标准”测试。 目的 研究 FA 中染色体脆性的变异性、诊断意义和临床影响。 方法 数据来自 198 个 DEB 诱导的染色体脆性 在患有和不患有 FA 的患者中进行测试，其中可以获得有关遗传亚型、细胞对 MMC 的敏感性和临床数据的信息。结果 这个大型系列可以量化 FA 患者和正常人群之间 ICL 敏感性的变异性和重叠水平。提出了一种新的染色体脆性指数，该指数提供了一个截止诊断水平，以明确地区分 FA 患者（包括马赛克）和非 FA 个体。还分析了自发染色体脆性及其与 DEB 诱导脆性的相关性，表明尽管两个变量相关，但 54% 的 FA 患者不存在自发脆性。数据揭示了畸形与 ICL 诱导剂敏感性之间的相关性。当分析仅限于 FA-A 补充组的患者时，这种相关性也具有统计学意义。最后，染色体脆性与血液病的发病年龄无关。结论本研究提出了一种新的染色体脆性指数，并表明胚胎发育过程中的基因组不稳定可能与 FA 畸形有关，而 DEB 诱导的 T 细胞染色体断裂对血液病没有预后价值。
Background Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) is the 'gold standard' test for the diagnosis of FA.Objective To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA.Methods Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available.Results This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease.Conclusions This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.