Abstract：
Acquired aplastic anemia (AA) is a bone marrow failure disorder characterized by pancytopenia, and immunosuppressive therapy (IST) is the optional first-line management. Several studies identified the influencing factors on IST response; however, there are still a considerable number of patients suffering from poor prognoses. In this study, we enrolled 61 AA patients aged ≤ 40 years old, and whole-exome sequencing (WES) found unexpected high FANC heterozygous germline mutations (28/61, 45.9%). Patients with FANC mutations have a significantly lower absolute reticulocyte count and CD34+ % in the bone marrow and also lower 3-, 6-, and 9-month IST response than that without mutation, which were 0% vs. 25% (P = 0.017), 26.3% vs. 42.1% (P = 0.495), and 29.4% vs. 72.2% (P = 0.011), especially in anti-thymocyte globulin combined with the cyclosporin A (ATG + CsA) group, which were 0% vs.33.4% (P = 0.143), 25% vs.83.3% (P = 0.103), and 25% vs. 100% (P = 0.003), respectively. The event-free survival in the FANCwt group was also better than that in the FANCmut group (P = 0.016) and also showed in patients who received ATG + CsA treatment (P = 0.045). In addition, all the adverse effects of FANC germline mutation were not significant in stem cell-transplanted group. Our result indicated that the WES-based detection of FANC heterozygous germline mutations may have a great meaning in predicting IST response of acquired AA. This study was registered at chictr.org.cn (# ChiCTR2100054992).
摘要：
获得性再生障碍性贫血（AA）是一种以全血细胞减少为特征的骨髓衰竭疾病，免疫抑制治疗（IST）是可选的一线治疗。几项研究确定了IST反应的影响因素；然而，仍有相当多的病人预后不佳。在这项研究中,我们纳入61例AA患者，年龄≤40岁，全外显子组测序（WES）发现了意想不到的高FANC杂合种系突变（28/61，45.9%）。FANC突变患者的骨髓中网织红细胞绝对计数和CD34％显着降低，并且3-6-，和9个月的IST反应比没有突变的反应，其中0%与25%(P=0.017),26.3%vs.42.1%(P=0.495),和29.4%vs.72.2%(P=0.011),尤其是抗胸腺细胞球蛋白联合环孢素A(ATG+CsA)组,0%vs.33.4%(P=0.143)，25%vs.83.3%(P=0.103)，和25%vs.100%(P=0.003),分别。FANCwt组的无事件生存率也优于FANCmut组（P=0.016），并且在接受ATGCsA治疗的患者中也显示（P=0.045）。此外,FANC种系突变的所有不良反应在干细胞移植组中均不显著.我们的结果表明，基于WES的FANC杂合种系突变检测可能对预测获得性AA的IST反应具有重要意义。这项研究在chictr.org注册。cn(#ChiCTR2100054992)。
