摘要
目的 综合检测81例急性单核细胞白血病(acute monocytic leukemia,AML)患者多基因突变的发生率及突变类型,初步探讨其分子遗传学特征.方法 应用荧光原位杂交(fluorescence in situ hybridization,FISH)技术检测MLL基因;采用DNA联合测序技术对17种髓系肿瘤的相关基因进行突变检测.结果 在81例AML患者中,67例(82.7%)至少携带1处基因突变.突变检出率最高者为NPM1基因(n=18),其他突变检出率大于10%的基因依次为FLT3-ITD(n=16)、NRAS(n=16)、DNMT3A (n=15)、TET2(n=12)、RUNX1(n=11)、KRAS(n=9).在功能方面,参与DNA甲基化的表观遗传学调节基因的突变检出率最高,为38.27%,其次为酪氨酸受体基因(32.1%)、转录调节基因(28.4%)及RAS通路调控相关基因(24.7%).异常核型组以单基因突变为主,而正常核型组则以2个或以上的基因突变共存为主,且与NPM1、FLT3-ITD及DNMT3A有关,差异均有统计学意义(P<0.05).以染色体为基础进行风险度分层,中危组及高危组单基因突变者的完全缓解率分别为91.7%和87.5%,均高于多基因突变患者的57.6%和25.0%,且差异均有统计学意义(P=0.0319,0.0117).结论 大于80%的AML患者至少携带1处基因突变,多基因突变与MLL重排的叠加可能共同影响这类疾病的临床表型及预后.在相同的风险分层下,基因突变的数量与首次诱导缓解率呈负相关.
Objective To characterize the molecular genetics of 81 patients with acute monocytic leukemia(AML).Methods Fluorescence in situ hybridization(FISH)was employed to detect MLL rearrangements.Combined mutations of 17 genes were detected by DNA-based PCR and Sanger sequencing.Results Sixty seven patients were found to harbor at least 1 mutation.The most commonly mutated gene was NPM1(n=18),which was followed by FLT3-ITD(n=16),NRAS(n=16),DNMT3A(n=15),TET2(n=12),R UNX1(n=11)and KRAS(n=9)mutations.Based on the functions of mutated genes,the most frequently involved were genes involved in DNA methylation(38.27%),tyrosine kinase receptor signaling(32.1%),transcription regulation(28.4%),and RAS pathway(24.7%).Single gene mutation predominated in patient with abnormal cytogenetic,while coexistence of≥2 mutations have predominated in patient with normal cytogenetic findings.Stratified by cytogenetic findings,patients with single gene mutation(intermediate-risk group)had significantly higher complete remission(CR)rates than those with≥2 gene mutations(unfavorable-risk group)(91.7%vs.57.6%,87.5%vs.25.0%,P=0.0319,0.0117,respectively).Conclusion Over 80%of AML patients were found to harbor at least one mutation.Their clinical phenotype and prognosis may be impacted by the synergy of MLL rearrangement and multiple mutations.For patients under the same risk stratification,the number of mutations is reversely correlated with the CR rate.
作者
周峰
晁红颖
卢绪章
陈涛
杨建和
姜乃可
岑岭
周民
Zhou Feng;Chao Hongying;Lu Xuzhang;Chen Tao;Yang Jianhe;Jiang Naike;Cen Ling;Zhou Min(Depatment of Hematology,Changzhou Second People’s Hospital Affiliated to Nanjing Medical University,Changzhou,Jiangsu 213003,China.)
出处
《中华医学遗传学杂志》
CAS
CSCD
2019年第6期556-560,共5页
Chinese Journal of Medical Genetics
基金
国家自然科学基金(81500103)
江苏省自然科学基金(BK-20151230).
