Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects
Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects
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DOI：
10.1086/338934
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发表时间：
2002-03-01
影响因子：
9.8
通讯作者：
Feinberg, AP
中科院分区：
文献类型：
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作者：
DeBaun, MR;Niemitz, EL;Feinberg, AP
Beckwith-Wiedemann综合征(BWS)是一种先天性癌症易感综合征，与胚胎癌、巨舌症、巨大儿、耳窝或耳皱、中线腹壁缺陷有关。BW中最常见的体质异常是表观遗传学，涉及H19或LIT1的异常甲基化，这两种甲基化编码11p15上的未翻译RNA。我们假设不同的表观遗传学改变将与BWS的特定表型相关。为了验证这一假设，我们使用BWS注册中心进行了一项病例队列研究。队列包括92名BWS患者和H19和LIT1的分子分析，这些患者表现出与注册中心中无法获得生物样本的患者相同的临床表型频率。H19基因甲基化频率在癌症患者中为56%(9/16)，显著高于非癌症患者中的17%(13/76；P=0.002)，且癌症与LIT1基因改变无关。腹壁中线缺陷组和巨大儿组LIT1基因甲基化频率分别为65%(41/63)和60%(46/77)，明显高于无腹壁缺陷组的34%(10/29)和18%(2/11)(P=0.012和P=0.002)。此外，11p15的父本单亲二体(UPD)与半身性肥大(P=.003)、癌症(P=.03)和低血糖(P=.05)相关。这些结果定义了BWS的表观类型-表型关系，其中H19和LIT1的异常甲基化和UPD与癌症风险和特定的出生缺陷密切相关。
Beckwith-Wiedemann syndrome (BWS) is a congenital cancer-predisposition syndrome associated with embryonal cancers, macroglossia, macrosomia, ear pits or ear creases, and midline abdominal-wall defects. The most common constitutional abnormalities in BWS are epigenetic, involving abnormal methylation of either H19 or LIT1, which encode untranslated RNAs on 11p15. We hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, we performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS and molecular analysis of both H19 and LIT1, and these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biological samples were not available. The frequency of altered DNA methylation of H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P = .002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal-wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively (P = .012 and P = .002, respectively). Additionally, paternal uniparental disomy (UPD) of 11p15 was associated with hemihypertrophy (P = .003), cancer (P = .03), and hypoglycemia (P = .05). These results define an epigenotype- phenotype relationship in BWS, in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects.