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Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of TRIM28 provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis. [ABSTRACT FROM AUTHOR]

Wilms tumour (WT) is an embryonal tumour that recapitulates kidney development. The normal kidney is formed from two distinct embryological origins: the metanephric mesenchyme (MM) and the ureteric bud (UB). It is generally accepted that WT arises from precursor cells in the MM; however whether UB-equivalent structures participate in tumorigenesis is uncertain. To address the question of the involvement of UB, we assessed 55 Wilms tumours for the molecular features of MM and UB using gene expression profiling, immunohistochemsitry and immunofluorescence. Expression profiling primarily based on the Genitourinary Molecular Anatomy Project data identified molecular signatures of the UB and collecting duct as well as those of the proximal and distal tubules in the triphasic histology group. We performed immunolabeling for fetal kidneys and WTs. We focused on a central epithelial blastema pattern which is the characteristic of triphasic histology characterized by UB-like epithelial structures surrounded by MM and MM-derived epithelial structures, evoking the induction/aggregation phase of the developing kidney. The UB-like epithelial structures and surrounding MM and epithelial structures resembling early glomerular epithelium, proximal and distal tubules showed similar expression patterns to those of the developing kidney. These observations indicate WTs can arise from a precursor cell capable of generating the entire kidney, such as the cells of the intermediate mesoderm from which both the MM and UB are derived. Moreover, this provides an explanation for the variable histological features of mesenchymal to epithelial differentiation seen in WT. [ABSTRACT FROM AUTHOR]

The increased risk of several types of cancer in Klinefelter syndrome (47XXY) suggests that the extra X chromosome may be involved in the tumorigenesis associated with this syndrome. Here, we show that cancer cells (PSK-1) derived from a patient with Klinefelter syndrome (47XXY) showing loss of an inactive X chromosome subsequently gained active X chromosomes. We found that this abnormal X chromosome composition in PSK-1 is caused by a loss of an inactive X chromosome followed by multiplication of identical active X chromosomes, not by reactivation of an inactive X chromosome. Furthermore, we extended the characterization of loss-of-inactive X in a series of 22 female-derived cancer cell lines (eight breast cancer cell lines, seven ovarian cancer cell lines, and seven cervical cancer cell lines). The data demonstrate that loss-of-inactive X in the female-derived cancer cells is mainly achieved by loss of an inactive X chromosomes followed by multiplication of an identical active X chromosomes. However, distinctive pathways, including reactivation of an inactive X chromosome, are also involved in the mechanisms for loss-of-inactive X and gain-of-active X in female-derived cancer cells. The biological significance of the loss-of-inactive X and gain-of-active X in the oncogenesis of Klinefelter syndrome and female-derived cancer cells are discussed.Oncogene (2004) 23, 6163-6169. doi:10.1038/sj.onc.1207808 Published online 14 June 2004 [ABSTRACT FROM AUTHOR]

Presents research which identified the gene responsible for early-onset, diffuse gastric cancer. Prevalence of gastric cancer; Familial incidence of gastric cancer; Study of a large kindred from New Zealand; Results of genetic linkage analysis; Sequencing of the E-cadherin protein gene; Effects of diminished E-cadherin expression; Role of E-cadherin in gastric cancer; Molecular basis for gastric cancer.

Background: Variations in the international incidence of Wilms' tumour might be due to genetic factors. The maternal insulin-like growth factor 2 gene (IGF2) is imprinted in normal tissues, whereas in some Wilms' tumours and other tumour types the imprint is lost, leading to biallelic transcription of IGF2. We investigated whether the difference in incidence of Wilms' tumour between children of east-Asian descent and white children is due to variations in proportion of tumours with loss of IGF2 imprinting (IGF2 LOI).Methods: We assessed IGF2 LOI by use of an ApaI polymorphism in IGF2 exon 9 or quantitative PCR measuring DNA methylation of the H19 and KvDMR1 alleles. The frequencies of perilobar nephrogenic rests associated with Wilms' tumour were assessed histologically in Japanese children and children of white and east-Asian descent.Findings: IGF2 LOI was present in Wilms' tumours from predominantly white children from New Zealand (13 of 41 tumours) but absent in tumours from Japanese children (0 of 21 tumours; difference in proportions 0.32, 95% CI 0.07-0.52). Frequency of perilobar nephrogenic rests accompanying tumours from white American children (1192 of 5002, 24%) was significantly higher than in Japanese (one of 56, 1%, difference in proportions 0.22, 95% CI 0.14-0.25) and east-Asian American children (seven of 92, 8%, 0.16, 0.09-0.21).Interpretation: Wilms' tumours in the east-Asian population rarely arise from the IGF2 LOI mechanism frequently noted in white patients. Our findings that IGF2 LOI and perilobar nephrogenic rests associated with this mechanism arise at low frequency in Japanese and east-Asian American children lend support to this conclusion. Variation in frequency of this epigenetic mechanism provides one explanation for the difference in incidence of Wilms' tumour between populations. [ABSTRACT FROM AUTHOR]