Genetic mechanism of tumor-specific loss of 11p DNA sequences in Wilms tumor

The American Journal of Human Genetics (Impact Factor: 10.93). 09/1987; 41(2):202-17.
Source: PubMed


Wilms tumor, a common childhood renal tumor, occurs in both a heritable and a nonheritable form. The heritable form may occasionally be attributed to a chromosome deletion at 11p13, and tumors from patients with normal constitutional chromosomes often show deletion or rearrangement of 11p13. It has been suggested that a germinal or somatic mutation may occur on one chromosome 11 and predispose to Wilms tumor and that a subsequent somatic genetic event on the normal homologue at 11p13 may permit tumor development. To study the frequency and mechanism of such tumor-specific genetic events, we have examined the karyotype and chromosome 11 genotype of normal and tumor tissues from 13 childhood renal tumor patients with different histologic tumor types and associated clinical conditions. Tumors of eight of the 12 Wilms tumor patients, including all viable tumors examined directly, show molecular evidence of loss of 11p DNA sequences by somatic recombination (four cases), chromosome loss (two cases), and recombination (two cases) or chromosome loss and duplication. One malignant rhabdoid tumor in a patient heterozygous for multiple 11p markers did not show any tumor-specific 11p alteration. These findings confirm the critical role of 11p sequences in Wilms tumor development and reveal that mitotic recombination may be the most frequent mechanism by which tumors develop.

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    • "This patient has bilateral cryptorchidism and a horseshoe kidney and developed WT at 18 mo of age; the presence of a germ-line mutation is consistent with his presentation of genitourinary anomalies and the early age at WT diagnosis. Tumor tissue DNA from this patient is no longer available for study, although previous RFLP analysis demonstrated loss of heterozygosity for 1 lp markers flanking the WT1 gene as a result of a somatic recombination event (Dao et al. 1987, patient 4). "
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    ABSTRACT: The WT1 gene is known to play a role in at least some cases of Wilms tumor (WT). The first exon of the gene is highly GC rich and contains many short tandem di- and trinucleotide repeats, interrupted direct repeats, and CCTG (CAGG) motifs that have been identified as hotspots for DNA deletions. We have analyzed 80 WT patient samples for mutations in the first exon of WT1, either by SSCP analysis of the first 131 bp of the coding portion of WT1 exon 1 or by size analysis of a PCR product encompassing the coding region of exon 1 in addition to flanking noncoding regions. We report here the occurrence of somatic and germ-line deletion and insertion mutations in this portion of the gene in four WT patients. The mutations are flanked by short direct repeats, and the breakpoints are within 5 nt of a CCTG (CAGG) sequence. These data suggest that a distinctive mutational mechanism, previously unrecognized for this gene, is important for the generation of DNA mutations at the WT1 locus.
    The American Journal of Human Genetics 02/1995; 56(1):84-90. · 10.93 Impact Factor
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    • "Approximately 40% of Wilms tumors manifest loss of heterozygosity (LOH) for chromosome 1lp RFLP markers through one of several mechanisms (Dao et al. 1987; Mannens et al. 1988). LOH has been thought to represent a second genetic event, loss of a normal tumor-suppressor allele, and thereby to reveal the prior inactivation of the other allele (Cavenee et al. 1983). "
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    ABSTRACT: Wilms tumors commonly exhibit loss of heterozygosity for polymorphic DNA markers located on the short arm of chromosome 11 at band p15. In some instances, the deleted region does not include 11p13, the location of the WT1 gene, suggesting the existence of a second Wilms tumor gene on 11p. Both the exclusive loss of the maternally derived allele in Wilms tumors and the recent description of constitutional paternal isodisomy for this region in patients with either the Beckwith-Wiedemann syndrome (BWS) or isolated hemihypertrophy have suggested that this second locus is subject to sex-specific genomic imprinting. Given that one of these isodisomic patients had minimal congenital anomalies (hemihypertrophy), we hypothesized that a proportion of Wilms tumors which had not lost heterozygosity for 11p markers (about 60% of all cases) might have arisen consequent to 11p paternal heterodisomy and that patients constitutionally homozygous at 11p15 might harbor paternal isodisomy. We have analyzed 40 Wilms tumor cases to determine the parental origin of the child's 11p15 alleles. Paternal heterodisomy could be excluded in all 28 unilateral and 8/9 bilateral potential candidates. It is intriguing that somatic mosaicism for 11p paternal isodisomy was detected in one child with bilateral Wilms tumor and macroglossia. Isodisomy could only be excluded in one of the three possible cases. Thus, 11p paternal hetero- and isodisomy appear to be uncommon causes of non-anomaly-associated Wilms tumors but may be more frequent in Wilms tumor patients with BWS-associated anomalies.
    The American Journal of Human Genetics 03/1994; 54(2):282-9. · 10.93 Impact Factor
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    • "The observation of these germ-line deletions, the majority of which are de novo mutations, led to the hypothesis that a gene at 11pl3 was important in the etiology of WT. The presence of tumor-specific alterations , detected cytogenetically or molecularly as loss of heterozygosity at polymorphic 11p loci in one-half of all tumors, further implicated an 11p13 gene in tumorigenesis (Kaneko et al. 1981; Fearon et al. 1984; Koufos et al. 1984; Orkin et al. 1984; Reeve et al. 1984; Dao et al. 1987). These data, in addition to epidemiological observations on the age at onset and laterality of tumors, have led to the model that mutation of one 11pl3 allele and subsequent mutation or loss of the remaining normal allele are critical steps in the development of tumors (Knudson and Strong 1972). "
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    ABSTRACT: One-half of all cases of Wilms tumor (WT), a childhood kidney tumor, show loss of heterozygosity at chromosomal band 11p13 loci, suggesting that mutation of one allele and subsequent mutation or loss of the homologous allele are important events in the development of these tumors. The previously reported nonrandom loss of maternal alleles in these tumors implied that the primary mutation occurred on the paternally derived chromosome and that it was "unmasked" by loss of the normal maternal allele. This, in turn, suggests that the paternally derived allele is more mutable than the maternal one. To investigate whether germinal mutations are seen with equal frequency in maternally versus paternally inherited chromosomes, we determined the parental origin of the de novo germinal 11p13 deletions in eight children by typing lymphocyte DNA from these children and from their parents for 11p13 RFLPs. In seven of the eight cases, the de novo deletion was of paternal origin. The one case of maternal origin was unremarkable in terms of the size or extent of the 11p13 deletion, and the child did develop WT. Transmission of 11p13 deletions by both maternal and paternal carriers of balanced translocations has been reported, although maternal inheritance predominates. These data, in addition to the general preponderance of paternally derived, de novo mutations at other loci, suggest that the increased frequency of paternal deletions we observed is due to an increased germinal mutation rate in males.
    The American Journal of Human Genetics 08/1990; 47(1):155-60. · 10.93 Impact Factor
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