Showing papers by "Eric R. Fearon published in 1984"

Somatic deletion and duplication of genes on chromosome 11 in Wilms' tumours.

Abstract: One of the most provocative findings in tumour biology is the relationship between chromosomal changes and embryonal cancers in children. For example, children with the rare paediatric syndrome AGR triad (aniridia, genito-urinary abnormalities and mental retardation) often develop Wilms' tumours at a very early age and carry a germ-line deletion on the short arm of chromosome 11 (11p13). It has been suggested that the germ-line deletion 11p is the first of two or more steps to cancer in AGR children. If this were true, one might expect a similar deletion to arise somatically in the far more common isolated Wilms' tumours of children without AGR, as suggested by Knudson from epidemiological data. However, a chromosomal deletion on 11p was observed in only two of five such cases, while it was absent or seen inconsistently in others. We have now used a molecular genetic approach to determine whether Wilms' tumour cells possess somatic alterations at 11p loci. We have found somatic deletions of specific genes in four of six Wilms' tumours. Surprisingly, in all four cases, the deletions were associated with duplications leading to homozygosity of the non-deleted alleles in the tumour cells. As analogous observations were recently reported in retinoblastoma, the genetic events reported here may underlie the development of many such embryonal tumours in children.

c-Ha-ras-1 oncogene lies between beta-globin and insulin loci on human chromosome 11p.

Abstract: DNA sequence polymorphisms have been used to determine the linear order and recombinational distances separating the Harvey ras 1 oncogene (c-Ha-ras-1), beta-globin, insulin, and parathyroid hormone genes on the short arm of human chromosome 11. Our results indicate that c-Ha-ras-1 is closely linked to both the beta-globin locus (theta = .08 [8 centimorgans], lod score = 5.11) and the insulin locus (theta = .04 [4 centimorgans], lod score = 3.31). Furthermore, the probable order of these loci on chromosome 11p is centromere-parathyroid hormone-beta globin-c-Ha-ras-1-insulin.

Carbamoyl phosphate synthetase deficiency: dna analysis

Abstract: Carbamoyl phosphate synthetase deficiency (CPSD) is an autosomal recessive disorder of ureagenesis. Untreated patients with complete CPSD die as neonates of hyperammonemia. Since CPS is not expressed in amniocytes, prenatal detection is limited to in utero liver biopsy. To determine if the CPS genes are abnormal in affecteds we analyzed nuclear DNA prepared from leukocytes or fibroblasts by hybridization to rat and human CPS cDNA sequences. DNAs from 6 individuals affected with CPSD, 2 non-affected sibs and 2 controls were digested with Eco RI, Hind III or Pst I and hybridized to 32P labeled rat CPS cDNA. No variations in the number or size of hybridizing fragments were seen. To enable linkage studies DNAs from the 10 parents were digested with 12 different restriction endonucleases. Only after Bgl I digestion was a variation seen (23,15.5 and 13 kb bands in some versus 23 kb in others). Using a smaller human CPS cDNA we detected three patterns 23, 23+13 and 13 kb. In one family both parents had the 23+13, 2 affected sibs had only the 23 and a normal sib had only the 13 kb fragment(s) in agreement with simple Mendelian inheritance. In 2 other families the affected had only the 23 kb fragment. The affected children in the remaining 2 families had 23+13 or 13 kb patterns. Our studies suggest that 1) large deletions or insertions of the CPS genes were not detected; 2) the CPSD phenotype and the Bql I derived restriction fragments co-segregate and 3) genetic heterogeneity exists in CPSD.