与ELANE相关的中性粒细胞减少症的突变和临床结果的多样性。
The diversity of mutations and clinical outcomes for ELANE-associated neutropenia.
作者信息
Makaryan Vahagn, Zeidler Cornelia, Bolyard Audrey Anna, Skokowa Julia, Rodger Elin, Kelley Merideth L, Boxer Laurence A, Bonilla Mary Ann, Newburger Peter E, Shimamura Akiko, Zhu Bin, Rosenberg Philip S, Link Daniel C, Welte Karl, Dale David C
机构信息
aDepartment of Medicine, University of Washington, Seattle, USA bDepartment of Molecular Hematopoiesis, Kinderklinik, MedizinischeHochschule, Hannover cInternal Medicine II, University Hospital, Tübingen, Tübingen, Germany dDepartment of Medicine, University of Washington, Severe Chronic Neutropenia International Registry, Seattle ePediatric Hematology Oncology, University of Michigan, Ann Arbor fPediatric Hematology Oncology, Saint Joseph's Children's Hospital, Paterson gDepartments of Pediatrics and Cancer Biology, University of Massachusetts Medical School, Worcester hPediatric Hematology/Oncology, Fred Hutchinson Cancer Research Center, Seattle iBiostatistics Branch, National Cancer Institute at the National Institutes of Health, Division of Cancer Epidemiology & Genetics, Bethesda jDivision of Oncology, Washington University, St Louis, USA *Vahagn Makaryan and Cornelia Zeidler contributed equally to the writing of this article.
出版信息
Curr Opin Hematol. 2015 Jan;22(1):3-11. doi: 10.1097/MOH.0000000000000105.
PURPOSE OF REVIEW
Mutations in the gene for neutrophil elastase, ELANE, cause cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). This study summarized data from the Severe Chronic Neutropenia International Registry (SCNIR) on genotype-phenotype relationships of ELANE mutations to important clinical outcomes. We also summarize findings for ELANE mutations not observed in SCNIR patients.
RECENT FINDINGS
There were 307 SCNIR patients with 104 distinctive ELANE mutations who were followed longitudinally for up to 27 years. The ELANE mutations were diverse; there were 65 single amino acid substitutions; 61 of these mutations (94%) were 'probably' or 'possibly damaging' by PolyPhen-2 analysis, and one of the 'benign' mutations was associated with two cases of acute myeloid leukemia (AML). All frame-shift mutations (19/19) were associated with the SCN. The pattern of mutations in the SCN versus CyN was significantly different (P < 10), but some mutations were observed in both groups (overlapping mutations). The cumulative incidence of severe adverse events, that is, myelodysplasia, AML, stem cell transplantation, or deaths was significantly greater for patients with SCN versus those with CyN or overlapping mutations. Specific mutations (i.e. G214R or C151Y) had a high risk for evolution to AML.
SUMMARY
Sequencing is useful for predicting outcomes of ELANE-associated neutropenia.
综述目的
中性粒细胞弹性蛋白酶（ELANE）基因突变可导致周期性中性粒细胞减少症（CyN）和严重先天性中性粒细胞减少症（SCN）。本研究总结了严重慢性中性粒细胞减少症国际注册研究（SCNIR）中关于ELANE基因突变与重要临床结局的基因型-表型关系的数据。我们还总结了在SCNIR患者中未观察到的ELANE基因突变的研究结果。
最新发现
307例SCNIR患者有104种独特的ELANE基因突变，对其进行了长达27年的纵向随访。ELANE基因突变具有多样性；有65个单氨基酸替代；通过PolyPhen-2分析，其中61个突变（94%）“可能”或“可能具有破坏性”，并且其中一个“良性”突变与两例急性髓系白血病（AML）相关。所有移码突变（19/19）均与SCN相关。SCN与CyN的突变模式有显著差异（P<0.001），但两组中均观察到一些突变（重叠突变）。与CyN或重叠突变患者相比，SCN患者发生严重不良事件（即骨髓发育异常、AML、干细胞移植或死亡）的累积发生率显著更高。特定突变（即G214R或C151Y）演变为AML的风险较高。
总结
测序有助于预测ELANE相关中性粒细胞减少症的预后。
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