Rainier S, Johnson L A, Dobry C J, Ping A J, Grundy P E, Feinberg A P
Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor 48109.
Nature. 1993 Apr 22;362(6422):747-9. doi: 10.1038/362747a0.
Genomic imprinting, or parental allele-specific expression of genes, has been demonstrated at the molecular level in insects and mice but not in man. Imprinting as a potential mechanism of human disease is suggested by paternal uniparental disomy of 11p15 in Beckwith-Wiedemann syndrome and by maternal uniparental disomy of 15q11-12 in Prader-Willi syndrome. Beckwith-Wiedemann syndrome is characterized by multiorgan overgrowth and predisposition to embryonal tumours such as Wilms' tumour of the kidney. A loss of heterozygosity of 11p15 is also frequently found in a wide variety of tumours, including Wilms' tumour and lung, bladder, ovarian, liver and breast cancers; 11p15 also directly suppresses tumour growth in vitro. Two genes in this band, H19 and insulin-like growth factor-II (IGF2) undergo reciprocal imprinting in the mouse, with maternal expression of H19 (ref. 13) and paternal expression of IGF2 (ref. 14). Here we find that both of these genes show monoallelic expression in human tissues and, as in mouse, H19 is expressed from the maternal allele and IGF2 from the paternal allele. In contrast, 69% of Wilms' tumours not undergoing loss of heterozygosity at 11p showed biallelic expression of one or both genes, suggesting that relaxation or loss of imprinting could represent a new epigenetic mutational mechanism in carcinogenesis.
基因组印记，即基因的亲本等位基因特异性表达，已在昆虫和小鼠中得到分子水平的证实，但在人类中尚未证实。贝克威思-维德曼综合征中11p15的父源单亲二体性以及普拉德-威利综合征中15q11 - 12的母源单亲二体性提示印记可能是人类疾病的一种潜在机制。贝克威思-维德曼综合征的特征是多器官过度生长以及易患胚胎性肿瘤，如肾母细胞瘤。在包括肾母细胞瘤以及肺癌、膀胱癌、卵巢癌、肝癌和乳腺癌在内的多种肿瘤中也经常发现11p15杂合性缺失；11p15在体外也直接抑制肿瘤生长。该区域的两个基因，H19和胰岛素样生长因子-II（IGF2）在小鼠中呈现相互印记，H19为母源表达（参考文献13），IGF2为父源表达（参考文献14）。我们发现这两个基因在人类组织中均呈现单等位基因表达，并且与小鼠一样，H19从母源等位基因表达，IGF2从父源等位基因表达。相比之下，11p未发生杂合性缺失的肾母细胞瘤中有69%显示一个或两个基因的双等位基因表达，这表明印记的松弛或缺失可能代表致癌过程中一种新的表观遗传突变机制。
