PDF(600 KB)
儿童急性淋巴细胞白血病中RAS基因突变的检测及其临床意义
姚燕玲, 王西阁, 赵雪莲, 李帅全, 周玉洁, 徐一卓
中国当代儿科杂志 ›› 2022, Vol. 24 ›› Issue (3) : 309-313.
PDF(600 KB)
PDF(600 KB)
儿童急性淋巴细胞白血病中RAS基因突变的检测及其临床意义
Detection of RAS gene mutation and its clinical significance in children with acute lymphoblastic leukemia
目的 探讨RAS基因在儿童急性淋巴细胞白血病中的突变率及其临床意义。 方法 回顾性收集2015年1月至2020年1月于郑州大学第三附属医院收治的新确诊且完成二代测序的急性淋巴细胞白血病120例患儿病例资料，分析其临床及分子学特征，以及RAS基因突变对急性淋巴细胞白血病患儿总生存率的影响。 结果 120例患儿中，共有35例（29.2%）患儿伴有RAS基因突变，其中仅KRAS基因突变30例（25.0%），NRAS基因突变伴KRAS基因突变5例（4.2%）。全部NRAS基因突变及71%（25/35）KRAS基因突变位于第12、13号密码子。RAS基因突变在急性B淋巴细胞白血病中检出率为33.3%（35/105），未在急性T淋巴细胞白血病中检出。失访11例（9.2%），随访109例患儿中死亡16例（14.7%）。RAS基因突变患儿的2年总生存率低于RAS基因阴性患儿（P<0.05）。伴RAS基因突变急性淋巴细胞白血病患儿合并WT1基因过表达、初诊白细胞数计数>50×109/L时，预后更差（P<0.05）。 结论 RAS基因突变多发生于急性B淋巴细胞白血病，对预后有不良影响。
Objective To investigate the mutation rate of the RAS gene and its clinical significance in children with acute lymphoblastic leukemia. Methods A retrospective analysis was performed on the medical data of 120 children with newly diagnosed acute lymphoblastic leukemia, who were admitted to the Third Affiliated Hospital of Zhengzhou University from January 2015 to January 2020 and underwent next-generation sequencing. The clinical and molecular features were analyzed. The impact of RAS gene mutation on the overall survival rate was evaluated in these children. Results Among the 120 children, 35 (29.2%) had RAS gene mutation, 30 (25.0%) had KRAS gene mutation, and 5 (4.2%) had both NRAS and KRAS gene mutations. All NRAS mutations and 71% (25/35) of KRAS mutations were located at the 12th and 13th codons. RAS gene mutation was detected in 35 (33.3%) out of 105 children with B-lineage acute lymphoblastic leukemia, but it was not detected in those with acute T lymphocyte leukemia. Of all the children, 11 (9.2%) were lost to follow-up, and among the 109 children followed up, 16 (14.7%) died. The children with RAS gene mutation had a significantly lower 2-year overall survival rate than those without RAS gene mutation (P<0.05). The prognosis of children with RAS gene mutation combined with WT1 overexpression and WBC>50×109/L at diagnosis was worse (P<0.05). Conclusions RAS gene mutation is commonly observed in children with B-lineage acute lymphoblastic leukemia and may have an adverse effect on prognosis.
急性淋巴细胞白血病 / RAS基因 / 突变 / 预后 / 儿童
Acute lymphoblastic leukemia / RAS gene / Mutation / Prognosis / Child
1 袁向飞, 陆敏. Ras/MAPK与PI3K/Akt信号转导通路及其相互作用[J]. 国际检验医学杂志, 2006, 27(3): 261-263. DOI: 10.3969/j.issn.1673-4130.2006.03.025.
2 郭雨声, 张如意, 贾舒婷, 等. 原癌基因Ras诱导的衰老与逃逸衰老机制的研究进展[J]. 生物化学与生物物理进展, 2016, 43(7): 652-660. DOI: 10.16476/j.pibb.2016.0095.
3 Scheidig AJ, Burmester C, Goody RS. The pre-hydrolysis state of p21ras in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins[J]. Structure, 1999, 7(11): 1311-1324. PMID: 10574788. DOI: 10.1016/s0969-2126(00)80021-0.
4 Buhrman G, Holzapfel G, Fetics S, et al. Allosteric modulation of Ras positions Q61 for a direct role in catalysis[J]. Proc Natl Acad Sci U S A, 2010, 107(11): 4931-4936. PMID: 20194776. PMCID: PMC2841912. DOI: 10.1073/pnas.0912226107.
5 Quinlan MP, Settleman J. Isoform-specific ras functions in development and cancer[J]. Future Oncol, 2009, 5(1): 105-116. PMID: 19243303. DOI: 10.2217/14796694.5.1.105.
6 吴君颖, 李冰, 贾玉娇, 等. 骨髓纤维化患者RAS基因突变特征及其预后意义[J]. 中华血液学杂志, 2020, 41(12): 989-995. PMID: 33445845. PMCID: PMC7840545. DOI: 10.3760/cma.j.issn.0253-2727.2020.12.004.
7 黄慧君, 李冰, 秦铁军, 等. 骨髓增生异常综合征RAS基因突变的分子学特征及预后意义[J]. 中华血液学杂志, 2020, 41(9): 723-730. PMID: 33113603. PMCID: PMC7595862. DOI: 10.3760/cma.j.issn.0253-2727.2020.09.004.
8 Lübbert M, Mirro JJ, Miller CW, et al. N-ras gene point mutations in childhood acute lymphocytic leukemia correlate with a poor prognosis[J]. Blood, 1990, 75(5): 1163-1169. PMID: 2407301. DOI: 10.1182/blood.V75.5.1163.1163.
9 Dunna NR, Vuree S, Anuradha C, et al. NRAS mutations in de novo acute leukemia: prevalence and clinical significance[J]. Indian J Biochem Biophys, 2014, 51(3): 207-210. PMID: 25204082.
10 Wiemels JL, Zhang Y, Chang J, et al. RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia[J]. Leukemia, 2005, 19(3): 415-419. PMID: 15674422. DOI: 10.1038/sj.leu.2403641.
11 Perentesis JP, Bhatia S, Boyle E, et al. RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia[J]. Leukemia, 2004, 18(4): 685-692. PMID: 14990973. DOI: 10.1038/sj.leu.2403272.
12 Wiemels JL, Kang M, Chang JS, et al. Backtracking RAS mutations in high hyperdiploid childhood acute lymphoblastic leukemia[J]. Blood Cells Mol Dis, 2010, 45(3): 186-191. PMID: 20688547. PMCID: PMC2943008. DOI: 10.1016/j.bcmd.2010.07.007.
13 Zhang JH, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia[J]. Nature, 2012, 481(7380): 157-163. PMID: 22237106. PMCID: PMC3267575. DOI: 10.1038/nature10725.
14 孔小行, 柴忆欢, 李建琴, 等. ras基因与儿童急性淋巴细胞白血病的关系[J]. 江苏医药, 2005, 31(5): 393-395. DOI: 10.3969/j.issn.0253-3685.2005.05.039.
15 Case M, Matheson E, Minto L, et al. Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia[J]. Cancer Res, 2008, 68(16): 6803-6809. PMID: 18701506. DOI: 10.1158/0008-5472.CAN-08-0101.
16 von Lintig FC, Huvar I, Law P, et al. Ras activation in normal white blood cells and childhood acute lymphoblastic leukemia[J]. Clin Cancer Res, 2000, 6(5): 1804-1810. PMID: 10815901.
17 Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia[J]. Nat Genet, 2013, 45(3): 242-252. PMID: 23334668. PMCID: PMC3919793. DOI: 10.1038/ng.2532.
18 Zhang HH, Wang HS, Qian XW, et al. Ras pathway mutation feature in the same individuals at diagnosis and relapse of childhood acute lymphoblastic leukemia[J]. Transl Pediatr, 2020, 9(1): 4-12. PMID: 32154130. PMCID: PMC7036641. DOI: 10.21037/tp.2020.01.07.
19 Irving J, Matheson E, Minto L, et al. Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition[J]. Blood, 2014, 124(23): 3420-3430. PMID: 25253770. PMCID: PMC4246039. DOI: 10.1182/blood-2014-04-531871.
20 Driessen EMC, van Roon EHJ, Spijkers-Hagelstein JAP, et al. Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants[J]. Haematologica, 2013, 98(6): 937-944. PMID: 23403319. PMCID: PMC3669451. DOI: 10.3324/haematol.2012.067983.
21 Oshima K, Khiabanian H, da Silva-Almeida AC, et al. Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia[J]. Proc Natl Acad Sci U S A, 2016, 113(40): 11306-11311. PMID: 27655895. PMCID: PMC5056035. DOI: 10.1073/pnas.1608420113.
