Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition.

Abstract

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...

Altered patterns of retinoblastoma gene product expression in adult soft-tissue sarcomas

“…The histopathological and relevant clinical characteristics of this group of soft-tissue sarcomas are summarised in Table I (Hansen et al, 1985;Friend et al, 1986). This early observation led to questions concerning the potential role of RB in the tumorigenesis of sporadic bone and soft-tissue sarcomas.…”

“…Most of these secondary neoplasms are bone or soft-tissue sarcomas (Hansen et al, 1985). In contrast, secondary neoplasms are uncommon in patients with the sporadic form of the disease.…”

Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations

“…In fact, loss of function of the RB1 gene is associated not only with RB but also with a variety of other tumours, such as osteosarcoma, small cell lung carcinoma, bladder tumour, and breast carcinoma (Wadayama et al 1994;Lee et al 1988;Hansen et al 1985).…”

Evolving gene therapy approaches for osteosarcoma using viral vectors: Review

“…Mutations associated with pRb pathway are the most frequently observed changes in OS (6,37,51). Several groups have tried to restore the pRb pathway by the use of a replicationdeficient recombinant adenovirus vector encoding the full-length pRb (158) or p16INK4A (22).…”

“…Other abnormalities linked to a predilection for the development of OS include Paget disease and fibrous dysplasia. Furthermore, OS frequently occurs in patients with an inherited mutation in the retinoblastoma gene (Rb), since patients affected with hereditary Rb mutations have a 1000-fold higher change of developing OS (51).…”