Cytogenetic studies by the myeloma research team at the University of Arkansas for Medical Sciences (UAMS) as part of the clinical staging of more than 1,000 patients has led to the discovery that partial or complete deletions of chromosome 13 (c13) are associated with a grave prognosis even with tandem autotransplants, exceeding the clinical implications of other powerful prognostic variables, such as beta-2 microglobulin and C-reactive protein on multivariate analyses. Recent investigations applying molecular analyses such a comparative genomic hybridization and fluorescence in situ hybridization (FISH) have shown c13 deletions in up to 50% of patients, compared to 15% to 20% in G-banding. Importantly, RB deletion was associated with shorter event free and overall survival, representing the single most adverse feature in 100 patients receiving standard chemotherapy. The grave consequences of c13 deletion is consistent with loss of one or more myeloma tumor suppressor genes on this chromosome. Review of 145 G-banded myeloma karyotypes with c13 deletions revealed that band 13q14 is the likely site of the putative tumor suppressor gene, as this band is the minimally (???) deleted region and invovled in >90% of the cases. Triple-color interphase FISH analysis on 39 myeloma patients with a panel of molecular probes spanning the q arm of c13 has identified several deletion hotspots, 2 at 13q14 and 1 at 13q21. To confirm these results and to perform a more comprehensive analysis of 13q deletion frequencies of myeloma patients entering SWOG 9321, interphase FISH with a panel of molecular probes specific for these molecular deletion hotspots will be conducted and extensive statistical analyses will be performed to discover the true incidence of c13 deletion frequency and patterns and whether c13 deletion is the most relevant correlate with prognosis in this disease. UAMS serves as the central repository for all bone marrow biopsies from this intergroup trial (>600 patients), performing histological evaluation (Bartl Grading) to determine prognostic implications for outcome. Using new techniques developed to perform FISH analyses on paraffin-embedded bone marrow biopsy material, an unprecedented opportunity exists to apply state-of-the art molecular technology to archived bone [marrow] specimens from this trial, and to correlate findings and prognosis, with the efforts of the Chief Statistician for this intergroup trial.
Three aims are proposed.
Specific Aim 1 : Determine the true incidence and pattern of c13 deletions in bone marrow biopsies from patients with myeloma enrolled in SWOG 9321 using triple color interphase FISH.
Specific Aim 2 : Determine the relationship of chromosome 13 deletions to standard prognostic indicators.
Specific Aim 3 : Evaluate whether chromosome 13 deletions correlate with clinical outcome (complete remission, event free survival, and overall survival).
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