儿童急性淋巴细胞白血病关联基因的SNP风险预测

发布时间：2018-06-09 14:03

本文选题：急性淋巴细胞白血病 + 儿童　；参考：《浙江大学》2016年硕士论文

【摘要】：目的:急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)是儿童期最常见的恶性肿瘤,多发于2-5岁幼儿。虽然ALL的病因及发病机制仍不明确,但多认为是受遗传因素和环境因素的共同影响。我们通过文献筛选出与欧洲儿童ALL有关联性的 7 个基因(ARID5B,CDKN2A,CEBPE,IKZF1,INTS10,OR8U8,TP63),并探讨这7个基因的8个单核苷酸多态性位点(ARID5B基因rs7089424和rs10994982、CDKN2A 基因 rs3731217、CEBPE 基因 rs4982731、IKZF1 基因rs11978267、INTS10 基因 rs920590、OR8U8 基因 rs1945213、TP63 基因 rs17505102)与中国汉族儿童ALL的关联性,从而有助于进一步阐明ALL的发病机制。方法:收集我院2015年6月-2015年12月期间入院的190例ALL患儿的血标本,提取DNA,并采用PCR结合质谱方法检测7个基因(ARID5B、IKZF1、CEBPE、CDKN2A、TP63、OR8U8、INTS10)的 8 个单核苷酸多态性位点(rs10994982,rs7089424,rs3731217,rs4982731,rs11978267,rs920590,rs1945213,rs17505102),并以270例非ALL儿童为对照组。之后应用统计学分析这8个单核苷酸多态性位点与儿童ALL相关性以及同一基因不同基因型与儿童ALL易感性的关系。结果:190例ALL患儿中,3-6岁患儿70例(约占36.8%),其中儿童ALL的两大主要遗传学分型-超二倍体(染色体数目50条)和TEL/AML融合基因,其检出率分别为18.4%和17.9%。对病例组和正常对照组的8个单核苷酸多态性位点的基因频率及基因型进行统计学分析,发现ARID5B基因rs10994982 A风险等位基因和rs7089424 G风险等位基因在病例组和正常对照组之间分布具有统计学差异(rs10994982,P=0.003;rs7089424,P=0.001);ARID5B 基因 rs10994982 的基因型AG、AA、GG以及ARID5B基因rs7089424的基因型TT、GG、GT在病例组和正常对照组中的分布具有统计学差异(rs10994982,P=0.0014;rs7089424,P=0.0071)。对这8个单核苷酸多态性位点与ALL的临床危险度、免疫分型以及细胞遗传学分型进行统计学分析发现,ARID5B基因rs10994982的AA基因型和rs7089424的GT/GG基因型与中国儿童中危组和低危组的ALL有显著关联性(rs10994982 中危组 OR=2.437,95%CI=1.168-5.085,低危组 OR=3.550,95%CI=1.501-8.397;rs7089424 中危组 OR=1.969,95%CI=1.110-3.495,低危组OR=2.157,95%CI=1.130-4.115),而与高危组没有关联性。ARID5B 基因 rs10994982 AG/AA基因型和rs7089424GT/GG基因型与儿童B系淋巴细胞白血病(B-ALL)有关联性,而与儿童T系淋巴细胞白血病(T-ALL)没有显著关联(rs 10994982 B-ALL OR=1.724,95%CI=1.070-2.780,T-ALL OR=1.427,95%CI=0.391-5.204;rs7089424 B-ALL OR=1.841,95%CI= 1.215-2.790,T-ALL OR=0.985,95%CI=0.341-2.846)。ARID5B 基因 rs7089424 的 G 风险等位基因与儿童 B-ALL超二倍体的发病风险有显著相关性(P0.05),ARID5B基因rs10994982的A风险等位基因与儿童ALL的细胞遗传学分型并无明显的相关性。CDKN2A基因rs3731217、CEBPE 基因 rs4982731、IKZF1 基因 rs11978267、INTS10 基因 rs920590、OR8U8基因rs1945213和TP63基因rs17505102各自的风险等位基因频率和基因型频率在两组之间的分布结果均无统计学差异。结论:1、ARID5B基因的单核苷酸多态性位点rs7089424和rs10994982与儿童ALL易感性有关,同时也与儿童ALL临床危险度分型中的低危组和中危组相关,进一步分析发现这两个位点都与儿童B-ALL相关,而与T-ALL没有关联性。2、未发现 CDKN2A 基因 rs3731217、CEBPE 基因 rs4982731、IKZF1 基因rs11978267、INTS10 基因 rs920590、OR8U8 基因 rs1945213、TP63 基因 rs17505102单核苷酸多态性位点与中国儿童ALL有关联性。
[Abstract]:Objective: acute lymphoblastic leukemia (ALL) is the most common malignant tumor in childhood, mostly in 2-5 year old children. Although the etiology and pathogenesis of ALL is still not clear, it is considered to be the common influence of genetic and environmental factors. We have screened 7 of the correlation between the ALL and the European children. ARID5B, CDKN2A, CEBPE, IKZF1, INTS10, OR8U8, TP63), and explore the 8 single nucleotide polymorphic loci of these 7 genes (ARID5B gene rs7089424 and rs10994982, CDKN2A gene rs3731217. The association of ALL in children is helpful to further elucidate the pathogenesis of ALL. Methods: the blood samples of 190 ALL children hospitalized in our hospital during the period of December -2015 June 2015 were collected, DNA was extracted, and 8 single nucleotide polymorphisms (ARID5B, IKZF1, CEBPE, CDKN2A, TP63, OR8U8, and OR8U8) were detected by PCR combined mass spectrometry. S10994982, rs7089424, rs3731217, rs4982731, rs11978267, rs920590, rs1945213, rs17505102) and 270 non ALL children as the control group. Then statistical analysis was used to analyze the correlation between the 8 single nucleotide polymorphisms and children ALL, and the relationship between the same gene genotype and the susceptibility to ALL in children. Results: 190 cases of ALL children, 3-6 years old. There were 70 children (about 36.8%), of which two major genetic types of ALL in children were hyper diploid (chromosome number 50) and TEL/AML fusion gene. The detection rates were 18.4% and 17.9%., respectively, for the genetic frequency and genotype of 8 single nucleotide polymorphic loci in the case group and the normal control group, and the ARID5B gene rs109 was found. 94982 A risk alleles and rs7089424 G risk alleles have statistical differences between the case group and the normal control group (rs10994982, P=0.003; rs7089424, P=0.001), and the genotype AG, AA, GG, and the genotype of the ARID5B gene rs10994982 are distributed in the case group and the normal control group. Statistical differences (rs10994982, P=0.0014; rs7089424, P=0.0071). The statistical analysis of the 8 single nucleotide polymorphic loci and the clinical risk, immunophenotype and cell genetic classification of ALL found that the AA genotypes of the ARID5B gene rs10994982 and the GT/GG genotypes of rs7089424 were significant with those of Chinese children's middle and low risk groups and the ALL in the low risk group. Association (rs10994982 medium risk group OR=2.437,95%CI=1.168-5.085, low risk group OR=3.550,95%CI=1.501-8.397; rs7089424 medium risk group OR=1.969,95%CI=1.110-3.495, low risk group OR=2.157,95%CI=1.130-4.115), but not associated with high-risk group.ARID5B gene rs10994982 AG/AA genotype and rs7089424GT/GG genotype and child B lymphatic lymph node Cell leukemia (B-ALL) was associated with T lymphoblastic leukemia (T-ALL) in children (RS 10994982 B-ALL OR=1.724,95%CI=1.070-2.780, T-ALL OR=1.427,95%CI=0.391-5.204; rs7089424 B-ALL OR=1.841,95%CI= 1.215-2.790). There is a significant correlation with the risk of B-ALL hyper diploid in children (P0.05), and there is no significant correlation between the A risk alleles of the ARID5B gene rs10994982 and the cell genetic classification of children ALL,.CDKN2A gene rs3731217, CEBPE gene rs4982731, IKZF1 gene rs11978267, There was no statistical difference in the distribution of the rs17505102 risk allele frequencies and genotype frequencies between the two groups. Conclusion: 1, the single nucleotide polymorphism site rs7089424 and rs10994982 of the ARID5B gene are related to the susceptibility to ALL in children, and also related to the lower and middle risk groups of the children's ALL clinical risk risk classification. The step analysis found that these two loci were all associated with children's B-ALL, but not associated with T-ALL.2, no CDKN2A gene rs3731217, CEBPE gene rs4982731, IKZF1 gene rs11978267, INTS10 gene rs920590, OR8U8 gene polymorphic loci were associated with Chinese children.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R733.71

【参考文献】