目的：探究CEBPA基因双端突变与单端突变2种突变模式的伴随附加基因突变分布差异,并讨论其与患者预后间的潜在相关性。方法：对152例正常核型初发急性髓细胞白血病(acute myeloid leukemia,AML)患者中,25个AML驱动基因的热点区域进行二代深度测序,并结合一代测序验证检测突变位点,利用卡方检验或Fisher 检验对CEBPA基因双端突变和单端突变所伴随的附加基因突变情况进行统计分析。结果：152例正常核型的初发AML患者中,CEBPA基因双端突变43例(28.29%),CEBPA基因单端突变13例(8.55%)。携带CEBPA基因单端突变患者伴3个以上附加基因突变百分比高于CEBPA基因双端突变（P=0.043）。在携带CEBPA基因双端突变患者中,未发现伴NPM1基因突变,而在13例CEBPA基因单端突变患者中,有6例伴NPM1突变(P<0.001)。附加基因突变分布分析中,CEBPA基因单端突变患者伴更多的DNA甲基化修饰基因突变（DNMT3A、TET2、IDH1、IDH2）（P=0.046）;CEBPA基因单端突变伴随更多的叠加高危组基因突变（DNMT3A、FLT3-ITD、TP53）。结论：CEBPA单端突变比双端突变患者伴随更多的预示不良预后的附加突变,可能与CEBPA基因双端突变及单端突变2种突变模式的预后差异相关。
Objective: To investigate the different patterns of additional gene mutation accompanied with CEBPA biallelic or monoallelic mutations in patients with acute myeloid leukemia, which might be associated with different prognosis of these two kinds of mutation subtypes. Methods: A total of 152 newly diagnosed acute myeloid leukemia patients with normal karyotype were enrolled. The mutations in hot spot regions of 25 AML driver genes were screened using next-generation sequencing strategy and the discovered mutation sites were confirmed by Sanger sequencing. The difference in additional gene mutation patterns accompanied with CEBPA biallelic and monoallelic mutations were analyzed by Chi-square or Fisher's exact test. Results: In the 152 patients, CEBPA biallelic mutations were identified in 43(28.29%) cases and monoallelic mutations in 13(8.55%) cases. The ratio of more than 3 additional gene mutations in patients carried CEBPA monoallelic mutations (4 cases, 30.77%) was higher than that of the patients with CEBPA biallelic mutations (3 cases, 6.98%) (P=0.043). No NPM1 gene mutation was found in patients with CEBPA biallelic mutated, while near half of the patients (6 cases, 46.15%) had CEBPA monoallelic mutations accompanied with NPM1 mutation. CEBPA monoallelic mutated patients were more involved in genes of DNA methylation group (DNMT3A, TET2, IDH1, IDH2) than those with CEBPA biallelic mutation (7 cases, 53.85% vs 10 cases, 23.26%, P=0.046). Meanwhile, more high-risk genes (DNMT3A, FLT3-ITD, TP53) co-mutated were found in patients with CEBPA monoallelic mutations than those with CEBPA biallelic mutations. Conclusions: Compared with patients with CEBPA biallelic mutation, the CEBPA monoallelic mutation cohort have more additional gene mutations associated with adverse prognosis, and the different gene mutation patterns may lead to different prognosis. However, more large-scale investigations are needed to verify their clinical significance.
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