1q23 gain is associated with progressive neuroblastoma resistant to aggressive treatment

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Abstract
Neuroblastoma is one of the most common malignant tumors of childhood and is characterized by regressive and progressive disease. Genetic factors that define progression of neuroblastomas are still unknown. We performed comparative genomic hybridization (CGH) on 27 neuroblastomas and dual-color fluorescence in situ hybridization (FISH) to identify genetic aberrations associated with progressive neuroblastoma showing resistance to aggressive treatment. 17q21-q25 gains and MYCN amplification were associated with stage 4 neuroblastomas; however, these genetic aberrations had no significant relation to the progression of stage 4 neuroblastomas. A novel chromosomal gain at 1q21-q25 was found in 8 of 16 cases (50%) of stage 4 neuroblastoma. Gain of 1q21-q25 was observed in all of the progressive cases (8/8), which showed resistance to chemotherapy, including 5 fatal neuroblastomas in stage 4, whereas 1q21-q25 gain was not found in any of the 8 remission cases in stage 4. Survival analysis also showed that 1q21-q25 gain was associated with a poor outcome. High xenotransplantability in nude mice was observed for the tumors with 1q21-q25 gain (4/5; 80%). These data show that 1q21-q25 gain is strongly associated with progression of stage 4 neuroblastoma. Furthermore, by dual-color FISH analysis using cosmid clones, the 1q21-q25 gain was narrowed to increase in DNA copy number on 1q23 in the fatal type of stage 4 neuroblastoma showing this gain. These results suggest that DNA amplification at 1q23 may play a role in the development of progressive neuroblastoma in an advanced stage.