Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival.
Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival.
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DOI：
10.1158/1078-0432.ccr-11-1791
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发表时间：
2011-12-15
期刊：
影响因子：
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通讯作者：
NCRI Haematology Oncology Studies Group
中科院分区：
文献类型：
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作者：
Boyd KD;Ross FM;Walker BA;Wardell CP;Tapper WJ;Chiecchio L;Dagrada G;Konn ZJ;Gregory WM;Jackson GH;Child JA;Davies FE;Morgan GJ;NCRI Haematology Oncology Studies Group
对初诊骨髓瘤患者1号染色体短臂（1p）上存在反复缺失的区域进行了检测，目的是明确这些缺失并评估其对生存的影响。
对来自英国医学研究理事会骨髓瘤IX试验的患者样本进行了基因定位、基因表达、荧光原位杂交（FISH）和突变分析，并与临床结果数据相关联。
11%的病例中1p32.3缺失，在接受自体干细胞移植（ASCT）治疗的患者中，这种缺失与总生存期（OS）受损密切相关。在接受强度较低治疗的患者中，del(1)(p32.3)与不良无进展生存期（PFS）或总生存期无关。纯合缺失的靶点是CDKN2C，然而它在半合子缺失病例不良结局中的作用不太确定。1p22.1 - 21.2是最常缺失的区域，包含候选基因MTF2和TMED5。在这些基因中未发现突变。19%的病例中1p12缺失，在单变量分析中，这种缺失与总生存期受损有关。纯合缺失的靶点是FAM46C，3.4%的病例中该基因发生突变。当把FAM46C缺失或突变的病例一起考虑时，在强化治疗环境下它们与总生存期受损密切相关。
在接受ASCT的骨髓瘤患者中，1p32.3和1p12的缺失与总生存期受损有关。基于反复出现的纯合缺失和突变情况，FAM46C被确定为一个具有潜在致病和预后意义的基因。
Regions on 1p with recurrent deletions in presenting myeloma patients were examined with the purpose of defining the deletions and assessing their survival impact. Gene mapping, gene expression, FISH and mutation analyses were performed on patient samples from the MRC Myeloma IX trial and correlated with clinical outcome data. 1p32.3 was deleted in 11% of cases, and deletion was strongly associated with impaired overall survival (OS) in patients treated with autologous stem cell transplant (ASCT). In patients treated less intensively, del(1)(p32.3) was not associated with adverse progression free survival (PFS) or OS. The target of homozygous deletions was CDKN2C, however its role in the adverse outcome of cases with hemizygous deletion was less certain. 1p22.1-21.2 was the most frequently deleted region and contained the candidate genes MTF2 and TMED5. No mutations were identified in these genes. 1p12 was deleted in 19% of cases, and deletion was associated with impaired OS in univariate analysis. The target of homozygous deletion was FAM46C, which was mutated in 3.4% of cases. When cases with FAM46C deletion or mutation were considered together, they were strongly associated with impaired OS in the intensive treatment setting. Deletion of 1p32.3 and 1p12 were associated with impaired OS in myeloma patients receiving ASCT. FAM46C was identified as a gene with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations.