Genome-wide loss of maternal alleles in a nephrogenic rest and Wilm's tumor from a BWS patient

CRC Department of Cancer Genetics, Paterson Institute of Cancer Research, Christie (CRC) Research Trust, Manchester, UK.
Human Genetics (Impact Factor: 4.82). 07/1995; 95(6):651-6. DOI: 10.1007/BF00209482
Source: PubMed


A patient with Beckwith-Wiedemann syndrome (BWS) presented with Wilms' tumour. Examination of the nephrectomy specimen showed, in addition to the tumour, the presence of nephrogenic rests. Nephrogenic rests are thought to be precursor lesions from which a Wilms' tumour may develop. A molecular analysis examining the loss of constitutional heterozygosity (LOCH), initially for chromosome 11, was performed on peripheral blood, the normal kidney, nephrogenic rest and tumour material. The study was extended to include markers from all 23 chromosomes. At each informative, locus, LOCH of the maternal allele was shown in the nephrogenic rest and tumour material. In addition, the normal kidney displayed allele imbalance. It would appear from these results that either extensive LOCH across the genome was an early genetic event in the development of malignancy in this patient or that the tumour and rest developed from cells containing no maternal chromosomes. The apparent LOCH seen in the normal kidney sample implies that full reduction to homozygosity is consistent with a histologically normal appearance. Putative mechanisms to explain this phenomenon are discussed.

5 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the WT1 gene were anticipated to explain the genetic basis of the childhood kidney cancer, Wilms tumour (WT). Six years on, we review 100 reports of intragenic WT1 mutations and examine the accompanying clinical phenotypes. While only 5% of sporadic Wilms' tumours have intragenic WT1 mutations, > 90% of patients with the Denys-Drash syndrome (renal nephropathy, gonadal anomaly, predisposition to WT) carry constitutional intragenic WT1 mutations. WT1 mutations have also been reported in juvenile granulosa cell tumour, non-asbestos related mesothelioma, desmoplastic small round cell tumour and, most recently, acute myeloid leukemia.
    Human Mutation 02/1997; 9(3-3):209-25. DOI:10.1002/(SICI)1098-1004(1997)9:33.0.CO;2-2 · 5.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nephrogenic rests are the consequence of residual metanephric tissue in a fully developed kidney. They usually occur along the perimeter of a mature renal lobe (i.e., perilobar), within the lobe itself (i.e., intralobar), or both (i.e., combined). Nephrogenic rests can be grossly obvious or microscopically discrete. Nephroblastomatosis designates nephrogenic rests that are multifocal or diffuse, and implies more extensive disease. Universal (panlobar) nephroblastomatosis denotes complete replacement of the renal lobe by nephrogenic tissue. The fate of nephrogenic rests and nephroblastomatosis varies and includes obsolescence, sclerosis, dormancy, hyperplasia, or neoplasia. Evidence strongly suggests that neoplastic transformation of nephrogenic rests results in Wilms' tumor (nephroblastoma). Nephrogenic rests almost always occur in the setting of Wilms' tumor; perilobar rests show a strong association with synchronous bilateral Wilms' tumors, whereas intralobar rests are more strongly associated with metachronous tumors. Genetic studies have shown that nephrogenic rests often share many of the same chromosomal defects as Wilms' tumor, which provides further evidence that they are precursors to nephroblastoma. Thus, nephrogenic rests are recognized as clinically significant entities requiring adequate detection and close surveillance. Heightened awareness regarding the clinical relevance of nephrogenic rests and nephroblastomatosis (1) has led to improved detection of these precancerous lesions, (2) fostered more intensive investigation into their biologic behavior, and (3) initiated in-depth discussions about potentially new treatment regimens. The pathologists' ability to identify and detect nephrogenic rests has benefited from the more efficient Beckwith classification. Radiologists have deployed high-resolution radiologic/imaging modalities to improve detection of nephrogenic rests in situ. Clinicians and surgeons are more aware of the impact that nephrogenic rests have upon patient management. Despite this progress, more data is needed to further define these lesions.
    Advances in Anatomic Pathology 10/2001; 8(5):276-89. DOI:10.1097/00125480-200109000-00005 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously described the physical localization of a constitutional t(5;6)(q21;q21) in a patient (tumor cell sample designated as MA214) with bilateral Wilms tumor (WT). We have now physically refined the breakpoints and identified putative gene targets within this region. The translocation breakpoints are contained within a 2.5-Mbp region on 5q21 containing four candidate genes and a 1.3-Mbp region on 6q21 that contains three candidate genes. To explore the role of this region in WT genesis, we have performed loss of heterozygosity (LOH) analysis with markers flanking the translocation breakpoints in tumor from MA214 and a panel of sporadic WT. Alleles were retained for all informative markers used in the MA214 tumor. In sporadic tumors LOH was found in 6 of 63 (9.5%) and 5 of 62 (8%) informative cases for flanking markers D6S301 and D6S1592 on 6q21. LOH was found in 3 of 58 (5.2%) and 2 of 54 (3.6%) for flanking markers D5S495 and D5S409 on 5q21. These preliminary data suggest LOH at the t(5;6)(q21;q21) region is unlikely to be a mechanism for tumor development in MA214, but may be important for a subgroup of sporadic WT.
    Cancer Genetics and Cytogenetics 04/2003; 141(2):106-13. DOI:10.1016/S0165-4608(02)00669-6 · 1.93 Impact Factor
Show more