Gene Mutation Profile in Patients with Acquired Pure Red Cell Aplasia
Authors: Long Zhangbiao , Li Hongmin , Du Yali , Wang Zhao , Han Bing 
Published: October 2019

Abstract
Background: Although many clonal hematopoiesis were detected in bone marrow failure disorders such as myelodysplastic syndrome (MDS) and aplastic anemia (AA) recently, the gene mutation profile and association between gene mutations and pathogenesis of acquired pure red cell aplasia (aPRCA) is not yet defined.
Aims: To identify gene mutation spectrum of patients with aPRCA and the correlation between gene mutations and response to immunosuppressive therapy (IST).
Methods: Thirty-three newly diagnosed patients with aPRCA between 2014 and 2017 in Peking Union Medical College Hospital were enrolled in this study. Blood and buccal samples were collected before IST for gene mutation screening by whole exome sequencing. We selected 94 candidate genes which associated with other bone marrow failure for next analysis. Somatic genes which mutation in aPRCA (including nonsynonymous, splicing single-nucleotide variants or insertion/deletions which may affect protein function) but not in 1000 genomes were selected. Patients were treated with IST (cyclosporine A or sirolimus alone) for at least two years, and their clinical data pre and after therapy were documented. Correlations between gene mutations and response to IST were further investigated.
Results: There were twelve males and twenty-one females patients with the medium age of 62-year-old (18-77) in this study. Most patients were treated with cyclosporine A and a few patients with sirolimus due to impaired renal function. There were thirteen CR, eleven PR (ORR 72.7%) and nine NR in a medium of 8 (6-10) month. After excluding the germline mutations, twenty-nine mutations in nineteen genes were detected in twenty-one patients (64%). The mutated genes were associated with transcription (BCOR, BCORL1, RUNX1, etc.), signal transduction (CSMD1, JAK3, etc.), epigenetic regulation (ASXL1, ATRX, etc.), telomere regulation (RPL5), and RNA splicing (U2AF2) pathway, but some gene was undetermined (STK10). The hemoglobin and reticulocytes level at diagnosis didn't show difference in patients with different mutations, and those with BCOR or BCORL1 mutations had a similar response to IST compared with those with no mutations (CR: PR: NR 5:1:0 vs. 5:6:1, P=0.2354), but had a better response than those with other gene mutations (CR: PR: NR 5:1:0 vs. 3:4:8, P=0.0193). When patients with BCOR or BCORL1 mutations and with no mutations were taken together to compared with those with other mutations, we can see an even more significant difference in response to IST between the two groups (P=0.0073). Among patients with other mutated genes rather than BCOR or BCORL1, those with multiple mutations seemed to have a lower response than those with single mutation, although not significant (CR: PR: NR 2:4:5 vs. 1:0:3, P=0.3674). Age and the hemoglobin level at diagnosis, however, did not influence the response to IST.
Conclusion: Clonal gene mutations could be found in patients with aPRCA. Those with BCOR and BCORL1 mutations had a similar response to IST compared with those with no mutations, but had a better response than those with other mutations.

Disclosures
No relevant conflicts of interest to declare.