This is a proposal to positionally clone a tumor suppressor gene in 1p36 which is deleted in many neuroblastomas. The SRO for the deletion has been narrowed to between markers PLOD and D1S80, which is estimated to correspond to less than 5 Mb, and a translocation with a breakpoint mapping within the SRO has been identified.
Specific aim 1 is to continue to refine the SRO by using new patient material, and to develop a physical map of the region through saturation with STSs in the region, a radiation hybrid panel of 1p36, and YAC and PAC contig formation.
Specific aim 2 is to identify candidate genes in the region by testing candidate genes and ESTs assigned to 1p36 to see if they lie in the SRO, and by sequencing representative clones.
Specific aim 3 is to identify the neuroblastoma TSG by (1) screening candidates by sequence analysis for functional motifs (2) looking for homozygous deletions or rearrangements in primary tumors and cell lines (3) examining patterns of expression by Northern analysis and (4) looking for gene-specific mutations in tumors and cell lines by transcription and translation assays in vitro and (4) transfer of strong candidate genes into a neuroblastoma cell line with deletion of 1p36. The final specific aim is to clone and characterize the neuroblastoma TSG and use transgenic mice experiments to determine gene function.
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