Clinical significance of somatic mutation in unexplained blood cytopenia
Clinical significance of somatic mutation in unexplained blood cytopenia
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DOI：
10.1182/blood-2017-01-763425
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发表时间：
2017-06-22
期刊：
影响因子：
20.3
通讯作者：
Cazzola, Mario
中科院分区：
文献类型：
--
作者：
Malcovati, Luca;Galli, Anna;Cazzola, Mario
不明原因的血细胞减少症，特别是贫血症，往往发生在老年人身上。这些血细胞减少症和骨髓肿瘤如骨髓增生异常综合征之间的关系目前尚不清楚。我们研究了一个不明原因血细胞减少症患者的前瞻性队列，目的是评估体细胞突变对识别患有骨髓肿瘤或有发生骨髓肿瘤风险的受试者的预测价值。该研究包括683名连续患者的学习队列，调查原因不明的血细胞减少症，以及190名疑似骨髓肿瘤患者的验证队列。使用粒细胞DNA，我们寻找40个基因的体细胞突变，这些基因在骨髓恶性肿瘤中反复突变。总体而言，435/683例患者在这些基因中的至少一个中携带体细胞突变。携带变异等位基因频率>= 0.10的体细胞突变，或携带2个或更多突变，对诊断髓系肿瘤的阳性预测值分别等于0.86和0.88。涉及TET 2、DNMT 3A或ASXL 1的剪接体基因突变和互补突变模式对髓系肿瘤的阳性预测值范围为0.86至1.0。在诊断结果不确定的受试者中，携带1个或多个体细胞突变与随访期间发生髓系肿瘤的可能性高相关（风险比5 13.9，P <0.001）。突变分析的预测值在独立验证队列中得到证实。这项研究的结果表明，外周血粒细胞的突变分析可能会显着提高目前的诊断方法不明原因的血细胞减少症，更普遍的骨髓肿瘤的诊断准确性。
Unexplained blood cytopenias, in particular anemia, are often found in older persons. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. We studied a prospective cohort of patients with unexplained cytopenia with the aim to estimate the predictive value of somatic mutations for identifying subjects with, or at risk of, developing a myeloid neoplasm. The study included a learning cohort of 683 consecutive patients investigated for unexplained cytopenia, and a validation cohort of 190 patients referred for suspected myeloid neoplasm. Using granulocyte DNA, we looked for somatic mutations in 40 genes that are recurrently mutated in myeloid malignancies. Overall, 435/683 patients carried a somatic mutation in at least 1 of these genes. Carrying a somatic mutation with a variant allele frequency >= 0.10, or carrying 2 or more mutations, had a positive predictive value for diagnosis of myeloid neoplasm equal to 0.86 and 0.88, respectively. Spliceosome gene mutations and comutation patterns involving TET2, DNMT3A, or ASXL1 had positive predictive values for myeloid neoplasm ranging from 0.86 to 1.0. Within subjects with inconclusive diagnostic findings, carrying 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio 5 13.9, P < .001). The predictive values of mutation analysis were confirmed in the independent validation cohort. The findings of this study indicate that mutation analysis on peripheral blood granulocytes may significantly improve the current diagnostic approach to unexplained cytopenia and more generally the diagnostic accuracy of myeloid neoplasms.