Krona Cecilia, Ejeskär Katarina, Abel Frida, Kogner Per, Bjelke Jill, Björk Elin, Sjöberg Rose-Marie, Martinsson Tommy
Department of Clinical Genetics Institute for the Health of Women and Children, Göteborg University, Sahlgrenska University Hospital-East, Göteborg, Sweden.
Oncogene. 2003 Apr 17;22(15):2343-51. doi: 10.1038/sj.onc.1206324.
Deletion of a part of the short arm of chromosome 1 is one of the most common chromosomal rearrangements observed in neuroblastoma (NBL) tumors and it is associated with a poor prognosis. No NBL tumor suppressor gene has yet been identified in the region. Our shortest region of overlap of deletions, ranging from marker D1S80 to D1S244, was shown to partly overlap a 500 kb region that was homozygously deleted in a NBL cell line. We have screened seven genes known to reside in or very close to this overlap consensus region, UBE4B/UFD2, KIF1B, DFFA, PGD, CORT, PEX14, and ICAT, for coding mutations in NBL tumor DNA. A few deviations from the reference sequences were identified; most interestingly being a splice site mutation that was detected in UBE4B/UFD2 in a stage 3 NBL with a fatal outcome. This mutation was neither present in the patients constitutional DNA nor in any of 192 control chromosomes analysed. Also, the expression of UBE4B/UFD2 was markedly diminished in the high-stage/poor-outcome tumors as compared to the low-stage/favorable-outcome tumors. Overall, the number of amino-acid changes in the genes of the region was low, which shows that mutations in these genes are rare events in NBL development. Given the data presented here, UBE4B/UFD2 stands out as the strongest candidate NBL tumor suppressor gene in the region at this stage.
1号染色体短臂部分缺失是神经母细胞瘤（NBL）肿瘤中最常见的染色体重排之一，且与预后不良相关。该区域尚未鉴定出NBL肿瘤抑制基因。我们确定的最短缺失重叠区域，范围从标记D1S80到D1S244，显示部分重叠一个在NBL细胞系中纯合缺失的500 kb区域。我们筛选了已知位于该重叠共有区域内或非常接近该区域的7个基因，即UBE4B/UFD2、KIF1B、DFFA、PGD、CORT、PEX14和ICAT，以检测NBL肿瘤DNA中的编码突变。鉴定出了一些与参考序列的偏差；最有趣的是在1例3期NBL且预后不良的病例中检测到UBE4B/UFD2存在剪接位点突变。该突变既不存在于患者的基因组DNA中，也不存在于所分析的192条对照染色体中的任何一条上。此外，与低分期/预后良好的肿瘤相比，UBE4B/UFD2在高分期/预后不良的肿瘤中的表达明显降低。总体而言，该区域基因中的氨基酸变化数量较少，这表明这些基因的突变在NBL发展过程中是罕见事件。根据此处提供的数据，UBE4B/UFD2在现阶段是该区域最有力的NBL肿瘤抑制基因候选者。
