MYCN和PHOX2B基因联合血浆游离DNA检测在高危神经母细胞瘤危险度分层及预后评估中的作用  

The role of MYCN and PHOX2B gene combined with plasma cell-free DNA detection in risk stratification and predicting the prognosis of high-risk neuroblastoma

作　　者：岳志霞[1] 邢天禹 蒋持怡 王希思[2] 赵文[2] 段超[2] 苏雁[2] 金眉[2] 高超[1] 马晓莉[2] Yue Zhixia;Xing Tianyu;Jiang Chiyi;Wang Xisi;Zhao Wen;Duan Chao;Su Yan;Jin Mei;Gao Chao;Ma Xiaoli(Hematology Center,Beijing Key Laboratory of Pediatric Hematology Oncology National Key Discipline of Pediatrics(Capital Medical University)Key Laboratory of Major Diseases in Children,Ministry of Education Beijing Pediatric Research Institute,Beijing Children′s Hospital,Capital Medical University,National Center for Children′s Health,Beijing 100045,China;Department of Medical Oncology,Pediatric Oncology Center,Beijing Children′s Hospital,Capital Medical University,National Center for Children′s Health,Beijing Key Laboratory of Pediatric Hematology Oncology,Key Laboratory of Major Diseases in Children,Ministry of Education,Beijing 100045,China)

机构地区：[1]国家儿童医学中心,首都医科大学附属北京儿童医院血液病中心,儿童血液病与肿瘤分子分型北京市重点实验室,儿科学国家重点学科,儿科重大疾病研究教育部重点实验室,北京市儿科研究所血液疾病研究室,北京100045 [2]国家儿童医学中心,首都医科大学附属北京儿童医院儿童肿瘤中心肿瘤内科,北京市儿童血液肿瘤重点实验室,儿科重大疾病研究教育部重点实验室,北京100045

出　　处：《中华实用儿科临床杂志》2022年第4期290-294,共5页Chinese Journal of Applied Clinical Pediatrics

基　　金：北京市自然科学基金(7212032)。

摘　　要：目的探讨MYCN基因、PHOX2B基因及血浆游离DNA(cfDNA)水平用于高危神经母细胞瘤(NB)危险度分层及预后评估的作用和意义。方法对2017年8月至2018年12月首都医科大学附属北京儿童医院收治的94例高危NB患儿进行前瞻性研究,分别于初诊时、化疗4个疗程和6个疗程后检测MYCN基因、PHOX2B基因及cfDNA水平,观察治疗过程中3项指标的变化,采用χ^(2)检验和Kaplan-Meier生存分析法评价其与疗效的关系。结果94例患儿中MYCN基因扩增14例(14.9%),PHOX2B基因阳性76例(80.8%),cfDNA水平>100μg/L者56例(59.6%)。MYCN基因扩增患儿初诊高乳酸脱氢酶(LDH,≥1500 U/L)比例(6/14例)显著高于基因正常组患儿(9/80例)(P=0.009);PHOX2B基因阳性患儿多部位转移病例(54/76例)及高神经元特异性烯醇化酶(NSE,≥370μg/L)比例(37/76例)显著高于基因阴性组患儿(5/14例,2/14例)(P=0.015、0.020);cfDNA高水平患儿初诊高LDH及高NSE比例(13/37例,28/37例)显著高于cfDNA低水平组患儿(2/48例,10/48例)(均P<0.001)。治疗过程中,随着肿瘤负荷减小,PHOX2B基因拷贝数和cfDNA水平较初诊时显著降低[0(0~719.6)拷贝比1723.5(0~186000.0)拷贝;19.0(1.1~225.5)μg/L比200.6(8.0~5247.4)μg/L](均P<0.001)。初诊时,MYCN基因扩增组患儿2年无事件生存(EFS)率显著低于MYCN基因正常组患儿[(33.3±13.1)%比(58.5±7.1)%,P=0.020];PHOX2B基因阳性组患儿2年EFS率显著低于阴性组患儿[(47.9±7.1)%比(79.1±11.1)%,P=0.043];cfDNA高水平组(≥229.6μg/L)2年EFS率显著低于cfDNA低水平组[(38.6±9.8)%比(71.7±8.2)%,P=0.001]。6个疗程后PHOX2B基因阳性组患儿2年EFS率显著低于基因阴性组患儿[(16.7±14.4)%比(60.6±6.6)%,P=0.014];维持治疗前间碘苄胍(MIBG)核素扫描阳性组患儿2年EFS率显著低于阴性组患儿[(35.2±11.7)%比(65.8±7.1)%,P=0.037]。治疗过程中,MYCN基因和cfDNA水平与患儿预后无显著相关性。将6个疗程后的PHOX2B基因及维持治疗前MIBG结果联合分组进行生�Objective To explore the clinical significance of the MYCN gene,PHOX2B gene and plasma cell-free DNA(cfDNA)in risk stratification and predicting the prognosis of high-risk neuroblastoma(NB).Methods This was a prospective study involving 94 high-risk NB children admitted to Beijing Children′s Hospital,Capital Medical University from August 2017 to December 2018.Relative levels of MYCN and PHOX2B and cfDNA at diagnosis,and 4 and 6 cycles of chemotherapy were detected,and their differences were compared by the Chi-square test.Kaplan-Meier survival analysis was performed to explore their prognostic potential in high-risk NB.Results Among the 94 high-risk NB children,14 cases(14.9%)had MYCN amplification,76 cases(80.8%)had positive expression of PHOX2B and 56 cases(59.6%)had cfDNA level higher than 100μg/L.The proportion of high lactate dehydrogenase(LDH,≥1500 U/L)level in the MYCN gene amplification group(6/14 cases)was higher than that in the normal group(9/80 cases)(P=0.009).The proportion of multi-site metastasis(54/76 cases)and high neuron specific enolase(NSE)level(NSE≥370μg/L,37/76 cases)in PHOX2B positive group were significantly higher than those in the negative group(5/14 cases,2/14 cases)(P=0.015,0.020).The proportion of high LDH and high NSE in high cfDNA concentration(≥229.6μg/L)group(13/37 cases,28/37 cases)were significantly higher than those in low cfDNA concentration group(2/48 cases,10/48 cases)(all P<0.001).With the decreased tumor burden during the treatment,the copy number of PHOX2B gene and cfDNA level were significantly lower than those at the initial diagnosis[0(0-719.6)copies vs.1723.5(0-186000.0)copies;19.0(1.1-225.5)μg/L vs.200.6(8.0-5247.4)μg/L,all P<0.001].The 2-year event-free survival(EFS)rate of the MYCN gene amplification group was significantly lower than that of the normal group[(33.3±13.1)%vs.(58.5±7.1)%,P=0.020].The 2-year EFS rate of PHOX2B positive group was significantly lower than that of the negative group[(47.9±7.1)%vs.(79.1±11.1)%,P=0.043].EFS rate in high c

关 键 词：神经母细胞瘤 高危 微小残留病 MYCN基因 PHOX2B基因 血浆游离DNA 

分 类 号：R739.4[医药卫生—肿瘤]