Objective: To explore the clinical implications and prognostic value of TP53 gene mutation and deletion in patients with myelodysplastic syndromes (MDS) . Methods: 112-gene targeted sequencing and interphase fluorescence in situ hybridization (FISH) were used to detect TP53 mutation and deletion in 584 patients with newly diagnosed primary MDS who were admitted from October 2009 to December 2017. The association of TP53 mutation and deletion with several clinical features and their prognostic significance were analyzed. Results: Alterations in TP53 were found in 42 (7.2%) cases. Of these, 31 (5.3%) cases showed TP53 mutation only, 8 (1.4%) cases in TP53 deletion only, 3 (0.5%) cases harboring both mutation and deletion. A total of 37 mutations were detected in 34 patients, most of them (94.6%) were located in the DNA binding domain (exon5-8) , the remaining 2 were located in exon 10 and splice site respectively. Patients with TP53 alterations harbored significantly more mutations than whom without alterations (z=-2.418, P=0.016) . The median age of patients with TP53 alterations was higher than their counterparts[60 (21-78) years old vs 52 (14-83) years old, z=-2.188, P=0.029]. TP53 alterations correlated with complex karyotype and International prognostic scoring system intermediate-2/high significantly (P<0.001) . Median overall survival of patients with TP53 alterations was shorter than the others[13 (95%CI 7.57-18.43) months vs not reached, χ(2)=12.342, P<0.001], while the significance was lost during complex karyotype adjusted analysis in multivariable model. Conclusion: TP53 mutation was more common than deletion in MDS patients. The majority of mutations were located in the DNA binding domain. TP53 alterations were strongly associated with complex karyotype and always coexisted with other gene mutations. TP53 alteration was no longer an independent prognostic factor when complex karyotype were occurred in MDS.
目的： 探讨伴TP53基因异常骨髓增生异常综合征（MDS）患者的临床特征及预后。 方法： 回顾性分析2009年10月至2017年12月中国医学科学院血液病医院新诊断的584例原发性MDS患者临床资料，采用包含112个血液肿瘤相关基因的靶向测序技术进行突变分析，并采用间期荧光原位杂交（FISH）技术检测TP53基因缺失。分析TP53基因突变和（或）缺失与临床特征之间的关系及其对患者总生存（OS）的影响。 结果： 42例（7.2%）伴TP53基因异常，其中单纯基因突变31例（5.3%），单纯基因缺失8例（1.4%），同时伴有突变和缺失3例（0.5%）。34例伴TP53基因突变患者中共检测到37个TP53突变，其中35个位于DNA结合结构域（第5~8号外显子），1个位于第10号外显子，1个为剪切位点突变。伴TP53基因异常组的平均基因突变数目（2.52个）显著高于无异常组（1.96个）（z=-2.418，P=0.016）。伴TP53基因异常患者的中位年龄[60（21~78）岁]高于无异常患者[52（14~83）岁]（z=-2.188，P=0.029）；伴TP53基因异常组中复杂核型比例、IPSS较高危组（中危-2及高危）比例显著高于无异常组（P值均<0.001）。伴TP53基因异常组的中位OS期[13（95%CI 7.57~18.43）个月]较无异常组（未达到）显著缩短（χ(2)=12.342，P<0.001），但多因素模型纳入复杂核型进行校正后，TP53突变不再是独立预后因素。 结论： 伴TP53基因异常MDS患者中基因突变较基因缺失常见，突变位点主要分布于DNA结合结构域。TP53基因异常与复杂核型相关，且常与多个基因突变相伴出现。在多因素模型纳入复杂核型校正后，TP53基因异常则不再是独立的预后因素。.
Keywords: Deletion; Mutation; Myelodysplastic syndromes; Prognosis; TP53 gene.