Survivors of the heritable form of retinoblastoma subsequently develop second primary osteosarcomas at substantially greater frequency than either the general population or survivors of nonheritable retinoblastoma. Here we present molecular genetic evidence that the development of these two disparate tumor types involves specific somatic loss of constitutional heterozygosity for the region of human chromosome 13 that includes the RBI locus. Similar events occur during the genesis of nonheritable osteosarcoma but not in several other embryonal tumors or sarcomas. These findings suggest that a conceptual approach toward defining the number of genes whose recessive mutant forms predispose to cancer is the molecular genetic analysis of clinically associated tumor types. They also suggest that the molecular basis of mixed cancer families may be the differential expression of a single pleiotropic recessive mutation by tissue specific mitotic segregation abnormalities.Retinoblastoma is one of a group of childhood tumors to which predisposition can be inherited as an autosomal dominant trait (1). This form of the disease generally affects both eyes, whereas the spontaneous form usually affects a single eye. The occurrence of retinoblastoma as both heritable and sporadic forms has allowed detailed statistical analyses, which indicate a relationship between these two forms of the disease (2-5). A locus, RBJ, which plays a role in the development of this tumor, has been localized to the q14 band of human chromosome 13 through segregation analysis (6) and by the identification of specific deletions of this chromosomal region in some retinoblastoma patients or their tumors (7)(8)(9).A model to unify these observations has been proposed (10), based on the previous hypothesis that as few as two mutations are required for malignant transformation (2-4). In this model, bilateral retinoblastoma cases have inherited a germinal mutation of the RBJ locus, which predisposes each cell to transformation by a further event. Evidence has recently been presented that suggests that these predisposing mutations are recessive at the cellular level, are expressed upon loss of the homologous wild-type allele (10-14), and occur as germ-line events in heritable cases and somatic events in sporadic cases. Several somatic chromosomal mechanisms effect this loss, including nondisjunctional loss of the homolog carrying the wild-type allele, followed by reduplication of the mutant chromosome, and mitotic recombination between the two homologs (10); the net result is a cell that is homozygous for the mutant allele at the RBI locus (14).Advances in surgical and radiotherapeutic techniques have led to survival rates exceeding 90% for retinoblastoma patients. However, survivors of the heritable, but not the spontaneous, form are at a substantially increased risk for the development of independent, second tumors (15)(16)(17)(18)(19)(20). In a recent longitudinal survey of 693 bilateral retinoblastoma cases (20), 15% developed independent second pr...

Previous cytogenetic studies have indicated that a subset of large bowel adenomas have distal 1p deletions. We addressed this question by examining 70 sporadic polyps (63 adenomas, 5 hyperplastic polyps, and 2 polyps of undetermined histology) from 55 patients for alterations at eight loci on the short arm of chromosome 1 and found allelic imbalance (AI) or loss of one allele (LOH) in 14 (20%). The locus most frequently changed was MSI, which maps to 1p33-35. Fluorescence in situ hybridisation with centromeric and telomeric probes for chromosome 1, performed for 11 polyps, did not yield an abnormal number of signals, in accordance with the interpretation that the observed AI and LOH were the result of interstitial deletions in 1p. Whereas allelic imbalance at five other loci (mapping to 5q, 8p, 10p, 11p and 17q) was found less frequently, and then mainly in large (> 2 cm) tumours, the 1p alterations were equally distributed among small (< 1 cm) and large polyps. They were preferentially found in left-side tumours. Instability at microsatellite loci--the mutator phenotype--is demonstrated by shifts in the electrophoretic mobility of normal alleles. The mutator phenotype was first associated with hereditary nonpolyposis colorectal cancer but is also occasionally found in sporadic colorectal carcinomas; however, it is still uncertain when in the adenoma-carcinoma sequence in this type of genomic instability arises. We therefore looked for it at 12 dinucleotide repeat loci and found that seven tumours (six adenomas and one hyperplastic polyp) from seven patients had acquired new alleles not seen in the patients' corresponding normal DNA. Our results suggest that inactivation of a putative suppressor gene distally in chromosome arm 1p is an early event in colorectal tumourigenesis. They also show that microsatellite instability can be detected in large bowel polyps, indicating that this phenomenon, too, probably plays a pathogenic role for some colorectal tumours early in the adenoma-carcinoma sequence.

No abstract

No abstract

No abstract