Relaxation of imprinted genes in human cancer

Genomic imprinting, or parental allele-specific expression of genes, has been demonstrated at the molecular level in insects and mice^1,2 but not in man. Imprinting as a potential mechanism of human disease is suggested by paternal uniparental disomy of 11 p15 in Beckwith-Wiedemann syndrome ³ and by maternal uniparental disomy of 15ql1-12 in Prader-Willi syndrome⁴. Beckwith-Wiedemann syndrome is characterized by multiorgan overgrowth and predisposition to embryonal tumours such as Wilms⁹ tumour of the kidney⁵. A loss of heterozygosity of 11 p15 is also frequently found in a wide variety of tumours, including Wilms' tumour and lung, bladder, ovarian, liver and breast cancers^6-11; 11pl5 also directly suppresses tumour growth in vitro¹². 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 lip showed biallelic expression of one or both genes, suggesting that relaxation or loss of imprinting could represent a new epigenetic mutational mechanism in carcinogenesis.