Scott Richard H, Douglas Jenny, Baskcomb Linda, Huxter Nikki, Barker Karen, Hanks Sandra, Craft Alan, Gerrard Mary, Kohler Janice A, Levitt Gill A, Picton Sue, Pizer Barry, Ronghe Milind D, Williams Denise, Cook Jackie A, Pujol Pascal, Maher Eamonn R, Birch Jillian M, Stiller Charles A, Pritchard-Jones Kathy, Rahman Nazneen
Section of Cancer Genetics, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, SM2 5NG, UK.
Nat Genet. 2008 Nov;40(11):1329-34. doi: 10.1038/ng.243. Epub 2008 Oct 5.
Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor. We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.
印记11p15生长调控区域的结构异常会导致以生长紊乱为特征的综合征，其中一些综合征包括患威尔姆斯瘤的风险。我们探讨了它们对非综合征性威尔姆斯瘤的可能影响，并在437例散发性威尔姆斯瘤患者（无生长障碍特征）的基因组淋巴细胞DNA中，发现了13例（3%）存在11p15结构异常，其中双侧病例占12%（P = 0.001），在一个家族性威尔姆斯瘤家系中也有发现。220例对照中未检测到异常（P = 0.006）。发现的异常包括H19 DMR表位突变、11p15单亲二体以及H19 DMR印记中心突变（一个微插入和一个微缺失），从而确定微插入是一种新的印记中心突变类型。我们的数据确定11p15结构缺陷是威尔姆斯瘤最常见的已知病因之一，为印记破坏提供了机制性见解，并揭示了临床上重要的表观基因型-表型关联。对临床管理的影响表明，所有威尔姆斯瘤患者都应考虑进行11p15结构分析。
