Relaxation of imprinted genes in human cancer

Abstract

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.

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

“…The common expression patterns in TGCTs were biallelic expression of H19 and null expression of IGF2 in the present study (Table 1). The patterns of H19/IGF2 expression were in contrast to those in Wilms' tumors (Ogawa et al, 1993;Rainier et al, 1993;Moulton et al, 1994;Steenman et al, 1994;Taniguchi et al, 1995;Feinberg and Tycko, 2004).…”

“…Epigenetic alterations in the 11p15.5 imprinted gene cluster are frequent in human cancers and are associated with disordered imprinting of IGF2 and H19 (Ogawa et al, 1993;Rainier et al, 1993;Moulton et al, 1994;Steenman et al, 1994;Taniguchi et al, 1995;Feinberg and Tycko, 2004). Loss of imprinting leads to pathological biallelic expression of IGF2 in Wilms' tumors (Ogawa et al, 1993;Rainier et al, 1993).…”

“…Loss of imprinting leads to pathological biallelic expression of IGF2 in Wilms' tumors (Ogawa et al, 1993;Rainier et al, 1993). This abnormality in Wilms' tumors is inevitably linked to a gain in methylation, localized to the 5 0 sequences and transcribed region of the closely linked and reciprocally imprinted H19 gene (Moulton et al, 1994;Steenman et al, 1994;Taniguchi et al, 1995).…”

Loss of imprinting and allele switching of p73 in renal cell carcinoma

“…Biallelic expression of p73 could thus be an important step in tumorigenesis in the kidney. Switching of an imprinted gene from monoallelic expression in normal tissue to biallelic expression in cancer is called loss of imprinting (LOI) (Rainier et al, 1993). To determine if the biallelic expression of p73 in renal cell carcinoma was due to LOI, we investigated the imprinting status of the p73 gene.…”

“…LOI was ®rst discovered during studies of IGF2 allelic expression in Wilms' tumor (Rainier et al, 1993). Since then it has been described in several imprinted genes, including IGF2, HI9, IPW, and p57KIP2 (Ogawa et al, 1993;Hibi et al, 1996;Rachmilewitz et al, 1996;Thompson et al, 1996).…”