靶向测序检测511例骨髓增生异常综合征患者基因突变

Gene mutations from 511 myelodysplastic syndromes patients performed by targeted gene sequencing

目的探索中国骨髓增生异常综合征（MDS）患者基因突变特征。方法采用包含112个血液肿瘤相关基因的靶向测序技术对511例MDS患者进行基因突变检测，并回顾性分析其临床资料。结果全部511例MDS患者中，共检测到83个突变基因，439例（86％）患者伴有至少1个基因突变。对涉及的83个基因依据其功能进行分类，突变频率依次为表观遗传相关基因（50％）、剪接子相关基因（37％）、信号传导相关基因（34％）、转录因子（24％）和细胞周期与凋亡相关基因（17％）。不同亚型患者的平均基因突变数目分别为：难治性血细胞减少伴单系发育异常（RCUD）1．25个，难治性血细胞减少伴多系发育异常（RCMD）1．73个，难治性贫血伴环状铁粒幼红细胞（RARS）2．79个，难治性贫血伴原始细胞增多．1（RAEB-1）2．22个，RAEB-22．34个，MDS伴单纯5q-2．67个，MDS未分类（MDS-U）2．00个。U2AF1突变患者单纯＋8核型异常比例显著增高[Q〈0．001，OR=4．42（95％CI2．23—8．68）]，复杂核型比例显著减低[Q=0．005，OR=0．22（95％CI0．04—0．72）]。依据基因突变数目，将患者分为伴有0～1个基因突变组，伴有2个基因突变组和伴有3个及以上基因突变组，三组总生存（OS）差异具有统计学意义（P=0．041）。结论近九成的MDS患者伴有至少1个基因突变，表观遗传相关基因和剪接子相关基因是MDS最常受累基因。随着疾病的演进基因突变数增多，基因突变数目多的患者OS较差。

Objective To study the characteristics of gene mutations in Chinese myelodysplastic syndromes （MDS） patients. Methods A total of 511 Chinese patients with MDS performed 112-gene targeted sequencing were retrospectively analyzed. Results Eighty-three distinct mutant genes were found in 511 patients with MDS. Amongst these, the most frequent mutations was associated with epigenetics （50%）, followed by spliceosome （37%）, signal transduction （34%）, transcription factors （24%） and cell cycle/apoptosis （ 17%）. 439 subjects （86%） had at least one gene mutation. The mean number of mutations in refractory anemia with unilineage dysplasia （RCUD） was 1.25, refractory anemia with multilineage dysplasia （RCMD） was 1.73, refractory anemia with ring sideroblasts （RARS） was 2.79, refractory anemia with excess blasts- 1 （RAEB- 1） was 2.22, RAEB-2 was 2.34, MDS with isolated 5q- was 2.67, MDS, unclassified （MDS-U） was 2.00. U2AF1 mutant subjects were more likely to have isolated ＋8 [Q 〈 0.001, OR = 4.42 （95% CI 2.23 - 8.68） ] and less likely to have complex karyotypes [Q = 0.005, OR = 0.22 （95% CI 0.04 - 0.72） 1. According to the number of gene mutations, all subjects were categorized into three groups, namely group with 0 - 1 mutation, with 2 mutations and with three or more mutations. There was a significant difference in overall survival （OS） among three groups （P = 0.041 ）. Conclusion About 90% patients with MDS have at least one gene mutation. Genes associated with epigenetics and spliceosome are most common mutated genes in MDS. The increased numbers of gene mutations accompany with disease evolution and associate with poor prognosis.