A third Wilms' tumor locus on chromosome 16q.

Loss of heterozygosity studies have been used to identify chromosomal regions which are frequently deleted and thus indicate areas which may harbor tumor suppressor genes. As a result, both the WT1 gene located in chromosome 11p13 and an unidentified gene(s) within chromosome 11p15 have been implicated in Wilms' tumorigenesis. Cytogenetic and linkage studies suggest that additional non-chromosome 11 sites are involved in Wilms' tumor. Because these sites may also involve loss of heterozygosity, loci on 33 autosomal arms were screened for allele loss in a series of Wilms' tumors. We found that in addition to loss on chromosome 11p (11 of 25 informative tumors) there was significant loss on chromosome 16q (9 of 45 informative tumors), while the total frequency of allele loss excluding these loci was low (9 of 426 total informative loci). These data indicate that losses of both chromosome 11p and 16q alleles are nonrandom events and suggest that 16q is the location of a third tumor suppressor gene underlying Wilms' tumorigenesis. The parental origin of the lost chromosome 16q allele was determined in eight sporadic tumors. Alleles of paternal and of maternal origin were each lost in four sporadic tumors indicating that, unlike chromosome 11p, alleles of either parental origin are lost on 16q.

Harvey-ras allele deletion detected by in situ hybridization to Wilms' tumor chromosomes.

We have examined the chromosomes from a case of sporadic Wilms' tumor using in situ hybridization to determine whether the Ha-ras (c-Ha-ras 1) oncogene had been deleted as the result of a reciprocal chromosomal translocation between the short arm of chromosome 11 (breakpoint 11p13) and the long arm of chromosome 12 (breakpoint 12q13). Neither the derivative 11 nor derivative 12 chromosome hybridized significantly to the Ha-ras probe, which indicated that this cellular oncogene was deleted as a consequence of the translocation. This conclusion is supported by a Southern blot analysis which demonstrates loss of a Harvey-ras allele. These results support the view that the Ha-ras oncogene may be functionally involved in Wilms' tumor development.

Loss of a Harvey ras allele in sporadic Wilms' tumour.

Genomic changes within chromosome band 11p13 appear to have a role in the initiation of Wilms' tumour. The human Harvey ras oncogene, c-Ha-ras 1, has been located by Jhanwar et al. immediately adjacent to this region at band 11p14 .1, although several groups have assigned the gene more distally at band 11p15 . We have examined tumour DNA from two cases of sporadic Wilms' tumour, and report here that in both cases one of the two constitutional c-Ha-ras 1 alleles was absent. One tumour had a reciprocal translocation between the short arm of chromosome 11 (at band 11p13), and the long arm of chromosome 12, with no visible loss of chromosomal material. The loss of a c-Ha-ras 1 allele in association with this translocation indicates that a submicroscopic deletion had occurred. The resulting hemizygosity may have had a role in tumour initiation. Our results indicate that the c-Ha-ras 1 gene and the 'Wilms' tumour locus' may be in close proximity. It would, therefore, be premature to exclude the possibility that these two sites are functionally related.

3' BCR recombines with IGL locus in BCR-ABL-positive philadelphia-negative chronic myeloid leukemia.

We have isolated the 3' BCR breakpoint junction of a complex BCR-ABL1 rearrangement found in leukemic cells with a cytogenetically normal karyotype, and the corresponding germline fragment that spanned the 3' BCR recombination site. Fluorescence in situ hybridization localized the 3' BCR recombination site to 22q11, about 350-600 kb proximal to BCR. Restriction map and DNA sequence comparisons indicated that 3' M-Bcr had recombined at a site within the variable region (Itv Region IV) of the immunoglobulin lambda (IGL) locus. Somatic rearrangement of DNA sequences (variable, joining, and constant regions) within the IGL locus, as in other Ig and TCR loci, represents the basis for human antibody diversity. Misrecombination of these somatically rearranging sites has been associated with chromosomal rearrangements in lymphoid leukemia and lymphoma, but there are no previous descriptions of IGL involvement in genomic aberrations associated with myeloid leukemia. Genes Chromosomes Cancer 26:366-371, 1999.

Expression of insulin-like growth factor-II transcripts in Wilms' tumour.

Wilms' tumour probably arises from embryonal kidney cells and occurs in both hereditary and sporadic forms. Knudson and Strong have suggested that both forms of the disease are initiated by two mutational events. In the case of the inherited form, cytogenetic evidence indicates that a germline deletion of chromosome band 11p13 may correspond to one of the two mutations. DNA mapping evidence is consistent with the notion that the tumour susceptibility gene (Wg) on chromosome 11 is actually recessive. Comings has proposed that the dominantly inherited tumours may arise by the inactivation or loss of a diploid pair of regulatory genes which normally suppress the expression of a structural transforming gene (Tg). It has recently been suggested that the N-myc oncogene may serve as a transforming gene in retinoblastoma, although no such gene has yet been identified in Wilms' tumour. We now report that in four cases of Wilms' tumour, insulin-like growth factor-II (IGF-II) transcripts are highly elevated compared with the adjacent normal kidney. In addition, we have mapped the gene for IGF-II to chromosome band 11p14.1, which is in the immediate vicinity of Wg. These findings suggest that IGF-II may be involved in the aetiology of Wilms' tumour.