Joyce M. Rapaport

Homozygosity of Chromosome 13 in Retinoblastoma

We studied the frequency of chromosome 13 homozygosity in tumor tissue obtained directly from eyes harboring retinoblastomas. The data indicate that approximately half of all retinoblastomas are homozygous for large portions of 13q, that the homozygosity occurs in vivo and not as an event secondary to culture of the tumor cells, that chromosome 13 homozygosity is not correlated with the degree of histopathologic differentiation of the tumor, and that the homozygosity occurs in both sporadic and hereditary retinoblastomas. The development of chromosome 13 homozygosity may represent a fundamental event in the oncogenesis of a considerable number of retinoblastomas. This finding may have implications for the genetic counseling of patients with hereditary retinoblastoma. It may also be important in understanding the mechanism of oncogenesis of other tumors, especially hereditary tumors.

Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene

Abstract New germline mutations in the human retinoblastoma gene are known to arise preferentially on paternally derived chromosomes, but the magnitude of that bias has not been measured. We evaluated 49 cases with a new germline mutation and found that in 40 cases (82%) the mutation arose on the paternally derived allele. We also evaluated 48 cases likely to have a somatic initial mutation; in this group the initial mutation arose on paternal or maternal chromosomes with approximately equal frequency. There was no statistically significant difference in the average age of fathers of children with new paternal germline mutations from the average age of fathers of children with new maternal germline mutations or somatic initial mutations. Combining the data with that from previous reports from other groups, the proportion of new germline mutations arising on a paternally derived allele is 85% (based on 72 cases; 95% confidence interval = 76–93%). This number can be useful in the genetic counseling of some families with retinoblastoma.

Linkage of Genes for Human Esterase D and Hereditary Retinoblastoma

Determinations of esterase D isoenzymes in the members of a family with hereditary retinoblastoma gave results consistent with linkage between the loci for esterase D and retinoblastoma. This gene linkage allows the detection of gene carrier states in certain kindreds. We used this technique to predict that a 6-month-old boy carries the tumor-predisposing retinoblastoma gene.

Molecular Etiology of Low-Penetrance Retinoblastoma in Two Pedigrees

In one family with low-penetrance retinoblastoma, a germ-line deletion is shared by affected and unaffected, obligate carriers. The deletion encompasses exon 4 of the retinoblastoma gene and corresponds to a mutant protein without residues 127-166. In a second family, RFLP analysis shows that two distant relatives have independently derived mutations. These families, together with others reported elsewhere, indicate that attributes of alleles at the retinoblastoma locus specify penetrance.