National Cancer Institute®
Last Modified: August 1, 2002
UI - 12097293
AU - Zatyka M; da Silva NF; Clifford SC; Morris MR; Wiesener MS; Eckardt KU;
TI - Houlston RS; Richards FM; Latif F; Maher ER Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease.
SO - Cancer Res 2002 Jul 1;62(13):3803-11
AD - Section of Medical and Molecular Genetics, Department of Pediatrics and Child Health, University of Birmingham, The Medical School, Edgbaston, United Kingdom.
Germ-line mutations in the von Hippel-Lindau (VHL) tumor suppressor disease are associated with a high risk of retinal and cerebellar hemangioblastomas, renal cell carcinoma (RCC), and, in some cases, pheochromocytoma (PHE). In addition, somatic mutation or epigenetic inactivation of the VHL gene occurs in most clear cell RCCs. VHL protein (pVHL) has a critical role in regulating proteasomal degradation of the HIF transcription factor, and VHL inactivation results in overexpression of many hypoxia-inducible mRNAs including vascular endothelial growth factor (VEGF). To identify novel pVHL target genes we investigated the effect of wild-type (WT) pVHL on the expression of 588 cancer-related genes in two VHL-defective RCC cell lines. Expression array analysis identified nine genes that demonstrated a >2-fold decrease in expression in both RCC cell lines after restoration of WT pVHL. Three of the nine genes (VEGF, PAI-1, and LRP1) had been reported previously as pVHL targets and are known to be hypoxia-inducible. In addition, six novel targets were detected: cyclin D1 (CCND1), cell division protein kinase 6, collagen VIII alpha 1 subunit, CD59 glycoprotein precursor, integrin beta8, and interleukin 6 precursor IFN-beta2. We found no evidence that CCND1, cell division protein kinase 6, CD59, and integrin beta8 expression was influenced by hypoxia suggesting that pVHL down-regulates these targets by a HIF-independent mechanism. A type 2C pVHL mutant (V188L), which is associated with a PHE only phenotype (and had been shown previously to retain the ability to promote HIF ubiquitylation), retained the ability to suppress CCND1expression suggesting that loss of pVHL-mediated suppression of cyclin D1 is not necessary for PHE development in VHL disease. Other studies have suggested that: (a) genetic modifiers influence the phenotypic expression of VHL disease; and (b) polymorphic variation at a CCND1 codon 242 A/G single nucleotide polymorphism (SNP) may influence cancer susceptibility or prognosis in some situations. Therefore, we analyzed the relationship between CCND1 genotype and phenotypic expression of VHL disease. There was an association between the G allele and multiple retinal angiomas (P = 0.04), and risk of central nervous system hemangioblastomas (P = 0.05). These findings suggest that a variety of HIF-independent mechanisms may contribute to pVHL tumor suppressor activity and that polymorphic variation at one pVHL target influences the phenotypic expression of VHL disease.
UI - 11912179
AU - Bodmer D; Eleveld M; Kater-Baats E; Janssen I; Janssen B; Weterman M;
TI - Schoenmakers E; Nickerson M; Linehan M; Zbar B; van Kessel AG Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21).
SO - Hum Mol Genet 2002 Mar 15;11(6):641-9
AD - Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands. firstname.lastname@example.org
Previously, we described a family with a significantly increased predisposition for renal cell cancer co-segregating with a t(2;3)(q35;q21) chromosomal translocation. Several primary tumors of the clear cell type from different family members were analyzed at a molecular level. Loss of the derivative chromosome 3 was consistently found. In addition, different somatic Von Hippel Lindau (VHL) gene mutations were observed in most of the tumors analyzed, even within the same patient. Based on these results a multistep tumorigenesis model was proposed in which (non-disjunctional) loss of the derivative chromosome 3 represents an early event and somatic mutation of the VHL gene represents a late event related to tumor progression. More recently, however, we noted that these two anomalies were absent in at least one early-stage tumor sample that we tested. Similar results were obtained in another family with renal cell cancer and t(3;6)(q12;q15), thus suggesting that another genetic event may precede these two oncogenetic steps. We speculate that deregulation of a gene(s) located at or near the translocation breakpoint may act as such. In order to identify such genes, a detailed physical map encompassing the 3q21 breakpoint region was constructed. Through a subsequent positional cloning effort we found that this breakpoint targets a hitherto unidentified gene, designated DIRC2 (disrupted in renal cancer 2). Computer predictions of the putative DIRC2 protein showed significant homology to different members of the major facilitator superfamily (MFS) of transporters. Based on additional DIRC2 expression and mutation analyses, we propose that the observed gene disruption may result in haplo-insufficiency and, through this mechanism, in the onset of tumor growth.
UI - 12175530
AU - Marsh D; Zori R
TI - Genetic insights into familial cancers-- update and recent discoveries.
SO - Cancer Lett 2002 Jul 26;181(2):125-64
AD - Cancer Genetics, Kolling Institute of Medical Research and Department of Molecular Medicine, The University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Sydney, Australia. email@example.com
While the vast majority of cancers are believed to occur sporadically, most forms of cancer, both adult and paediatric, have a hereditary equivalent. In the case of adult malignancies, these include hereditary breast and ovarian cancer and syndromes such as the multiple endocrine neoplasias types 1 and 2 characterised by specific tumours of the endocrine gland system. In the case of paediatric malignancies, these include syndromes such as retinoblastoma and Wilms tumour. In a little over a single decade, we have seen a tremendous increase in the knowledge of the primary genetic basis of many of the familial cancer syndromes. The majority of familial syndromes are inherited as autosomal dominant traits including hereditary colon cancer and familial malignant melanoma, however, the genetics behind autosomal recessive disorders such as Bloom syndrome and Fanconi anaemia are also being elucidated. A third mode of inheritance less well understood in the setting of familial cancer is that of imprinting recently observed in a subset of families with inherited paraganglioma. In this review, we discuss 31 genes inherited in an autosomal dominant manner associated with 20 familial cancer syndromes. Genes inherited in an autosomal recessive manner linked to familial cancer syndromes are also discussed. The identification of genes associated with familial cancer syndromes has in some families enabled a 'molecular diagnosis' that complements clinical assessment and allows directed cancer surveillance for those individuals determined to be at-risk of disease.
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