ABSTRACT
Genomic imprinting is a reversible condition that causes parental-specific silencing of maternally or paternally inherited genes. Analysis of DNA and RNA from 52 human hepatocarcinoma samples revealed abnormal imprinting of genes located at chromosome 11p15 in 51% of 37 informative samples. The most frequently detected abnormality was gain of imprinting, which led to loss of expression of genes present on the maternal chromosome. As compared with matched normal liver tissue, hepatocellular carcinomas showed extinction or significant reduction of expression of one of the alleles of the CDKN1C, SLC22A1L, and IGF2 genes. Loss of maternal-specific methylation at the KvDMR1 locus in hepatocarcinoma correlated with abnormal expression of CDKN1C and IGF2, suggesting a function for KvDMR1 as a long-range imprinting center active in adult tissues. These results point to the role of epigenetic mechanisms leading to loss of expression of imprinted genes at chromosome region 11p15 in human tumors.
Subject(s)
Carcinoma, Hepatocellular/genetics , Chromosomes, Human, Pair 11 , Gene Silencing , Genomic Imprinting , Liver Neoplasms/genetics , Adult , Carcinoma, Hepatocellular/pathology , Chromosome Mapping , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/genetics , DNA Methylation , Female , Gene Expression Regulation, Neoplastic , Genes, MDR , Heterozygote , Homozygote , Humans , Insulin-Like Growth Factor II/genetics , Liver Neoplasms/pathology , MaleABSTRACT
Wilms' tumor (WT) is caused by abnormal development of embryonal kidney cells. WT cells are frequently affected by deletions or functional inactivation of maternal alleles at chromosome 11p15, which indicates that the loss of maternally expressed genes in this region plays an important role in WT pathogenesis. Maternally expressed genes indeed exist within an imprinted region at 11p15.5. Among these, BWR1C is highly expressed in fetal but not in adult kidney, which suggests that it may fulfil an important role in kidney development. Here, we demonstrate that the lack of BWR1C expression is common in WT. Its homology with the proapoptotic gene TDAG51 suggests that the loss of BWR1C expression may be relevant in WT development. In addition, the analysis of the expression of other 11p15 imprinted genes and kidney-developmentally regulated genes indicates that IGF2 overexpression, inappropriate coexpression of RET and GDNF and, in some cases, down-regulation of CDKN1C may also play an important role in the pathogenesis of WT. Our results add new elements to the understanding of the biological basis of WT, which may have implications for WT diagnosis and therapy.
Subject(s)
Chromosomes, Human, Pair 11/genetics , Drosophila Proteins , Genomic Imprinting , Kidney Neoplasms/genetics , Kidney/metabolism , Nerve Growth Factors , Organic Cation Transport Proteins , RNA/genetics , Wilms Tumor/genetics , Adult , Cadherins/genetics , Cyclin-Dependent Kinase Inhibitor p57 , DNA-Binding Proteins/genetics , Female , Fetus , Gene Expression Regulation, Developmental , Gene Expression Regulation, Neoplastic , Glial Cell Line-Derived Neurotrophic Factor , Glial Cell Line-Derived Neurotrophic Factor Receptors , Humans , Kidney/embryology , Nerve Tissue Proteins/genetics , Neural Cell Adhesion Molecules/genetics , Nuclear Proteins/genetics , PAX2 Transcription Factor , Proteins/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-ret , Receptor Protein-Tyrosine Kinases/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/genetics , Tumor Cells, Cultured , WT1 ProteinsSubject(s)
Bacterial Proteins , Chromosome Mapping , Chromosomes, Human, Pair 11 , DNA-Binding Proteins/genetics , Genes, Tumor Suppressor/genetics , Nuclear Pore Complex Proteins , Nuclear Proteins/genetics , Blotting, Southern , Chromosomes, Artificial, Yeast/genetics , DNA Primers , Humans , Membrane Proteins/genetics , Neoplasm Proteins/genetics , Stromal Interaction Molecule 1ABSTRACT
Thirty-six young healthy patients developed a peculiar clinical syndrome affecting only one eye. The early stage of the disease was characterized by visual loss, vitritis, mild papilledema, and successive crops of multiple, evanescent, gray-white, deep, retinal lesions. Over a period of many months there developed widespread, diffuse and focal depigmentation of the pigment epithelium, retinal arterial narrowing, optic atrophy, severe visual loss, and electroretinographic changes. A motile, subretinal round worm, probably a Toxocara, was observed in two patients.
