DIFFERENTIATION AND NGF RECEPTOR FOR NEUROBLASTOMA.

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Germ line or acquired alterations of chromosome 13 have been associated with tumorigenesis for retinoblastoma, osteosarcoma, and alveolar rhabdomyoscaroma. Constitutional chromosomal deletions of 13ql4 are considered etiologic for retinoblastoma, whereas chromosome 13 DNA deletions in osteosarcomas have recently been detected. A cDNA, rb-1, which maps to 13ql4 and has been suggested as a tumor-suppressor gene, has been isolated, and studies to determine its role in other tumors are beginning. Cytogenetic studies of osteosarcomas indicate complex karyotypes and absence of normal chromosome 13s. Alveolar rhabdomyosarcomas have a translocation, t(2;13). with breakpoint at 13q14, suggesting involvement of rb-l or a closely linked locus. We Propose to determine whether osteosarcomas and rhabdomyosarcomas have alterations of a similar region of the genome in 13q14. We will explore how they relate to one another and to the rb-l locus for diagnostic purposes. Our specific aims are to: I. Examine the involvement of chromosome 13 in alveolar rhabdomyosarcoma using a combination of cytogenetic and molecular techniques Southern and Northern blotting using the rb.l probe will be performed. Anonymous polymorphic 13q Probes and Southern blot analysis will be used to examine hetero-versus homo-zygosity in matched tumor and normal tissues. II. Examine the integrity of chromosome 13 in osteosarcomas using a combination of cytogenetic and molecular techniques. Southern blotting and chromosomal in situ hybridization of the rb-l and anonymous Probes for 13q will be used to determine whether conversion to homozygosity is due to chromosome 13 loss or rearrangement. III. Characterize the chromosome 13 DNA sequences at or near the breakpoint for the t(2;13) of alveolar rhabdomyosarcoma. Production of a limited long-range restriction map of the region using pulsed-field gel electrophoresis, and comparison of tumor and normal germ-line DNA from the same patients will be required. Our unique ability to correlate molecular biologic investigation with classical cytogenetic studies, in a clinical setting will provide new information on the genetic etiology of these tumors and provide a molecular approach to their diagnosis.