Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Abstract

Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner. (Mol Cancer Res 2006;4(4):283 -92)

IGF2 and cancer

“…LOI is a common epigenetic abnormality in breast (Hartmann et al 2005), oesophageal (Zhao et al 2009) and ovarian cancer (Murphy et al 2006) and acute myeloid leukaemia (Wu et al 1997). In Wilms' tumours, there is increased IGF2 expression in 50% of cases, usually due to LOI (Reeve 1996).…”

Loss of imprinting of IGF2 correlates with hypomethylation of the H19 differentially methylated region in the tumor tissue of colorectal cancer patients

“…Alteration of the normal imprinting status is a common abnormality in embryonic and adult cancers, involving the loss of origin-specific gene expression, in a phenomenon known as loss of imprinting (LOI). LOI is found in various types of adult malignancies including ovarian (7,8), colon (9), lung (10) and bladder cancer (11), as well as chronic myelogenous leukemia (12).Insulin-like growth factor 2 (IGF2) is a maternally imprinted gene and encodes a fetal peptide hormone regulating cell proliferation and differentiation (13). IGF2 has four promoter regions and promoter 3 is the most active promoter in the fetal liver (14).…”

-thalassemia major evolution from -thalassemia minor is associated with paternal uniparental isodisomy of chromosome 11p15

“…Through proliferation, this clone became the only hemopoietic cell in the bone marrow and peripheral blood and resulted in the β-thalassemia major phenotype, a phenomenon found in a variety of malignancies. 16,17 We conclude that the patient's β-thalassemia major involved inheritance of paternal uniparental isodisomy of chromosome 11p15 harboring the HBB [c.52A>T] allele, which was mixed with β-thalassemia minor mosaicism caused by normal biparental inheritance. Though homozygosity of autosomal recessive gene mutations was described in uniparental disomy of other chromosomes, homozygosity of HBB gene mutations associated with paternal uniparental isodisomy of 11p15 is reported here for the first time.…”