S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Clinical Medical Sciences (임상의과학과) Theses (Ph.D. / Sc.D._임상의과학과)
Next Generation Sequencing Based Multi-Gene Mutation Analysis in Patients with Myelodysplastic Syndrome and Idiopathic Cytopenia of Undetermined Significance
골수형성이상증후군과 원인불명 혈구감소증 환자에서 차세대염기서열분석법을 이용한 다중 유전자 변이 분석
- 의과대학 임상의과학과
- Issue Date
- 서울대학교 대학원
- Myelodysplastic syndrome
- 학위논문 (박사)-- 서울대학교 대학원 : 임상의과학과, 2015. 2. 이동순.
- Introduction: Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid neoplasms characterized by cytopenias that are associated with impaired hematopoietic differentiation, and have a risk of progression to acute myeloid leukemia (AML). The development of high-throughput DNA sequencing technologies has uncovered many important new somatic mutations underlying the pathogenesis of MDS. Knowledge of the genetic basis of MDS allows more accurate diagnoses and better treatment choices. However, data on the genetic abnormalities of Korean MDS patients remain scarce. The aim of this study was to investigate the mutational profiles of Korean MDS patients using multi-gene panels based on next-generation sequencing.
Methods: A total of 162 patients diagnosed with different MDS subtypes and 36 patients with idiopathic cytopenia of undetermined significance (ICUS), were enrolled in this study. The MDS patients were diagnosed with the following subtypes: 28 refractory cytopenia with unilineage dysplasia (RCUD)
6 refractory anemia with ring sideroblasts (RARS)
29 refractory cytopenia with multilineage dysplasia (RCMD)
64 refractory anemia with excess blasts (RAEB)
14 MDS-unclassifiable (MDS-U)
5 myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN), and 16 AML evolved from previous MDS (MDS-AML). Targeted sequencing of 87 selected genes was performed, and the putative mutations were analyzed compared to a normal reference control population.
Results: Overall, 136/162 MDS patients (84.0%) and 25/36 (69.4%) ICUS patients harbored at least one mutation. The 10 most frequently mutated genes were ASXL1, TP53, U2AF1, DNMT3A, TET2, RUNX1, BCOR, FAT4, SRSF2, and NOTCH1. The most frequently mutated genes in ICUS patients were NFKBIE (mutated in 3 patients, 8.6%) and BCOR, BRD4, NOTCH1, and SAMHD1 (each mutated in 2 patients, 5.7%). The most frequent target functions of the mutated genes were transcription, RNA splicing, and DNA methylation. Interestingly, novel mutations in FAT4 were frequently found in our population. The number of mutations increased in patients with advanced stages of MDS (RAEB or AML from previous MDS). The mutations were associated with distinct cytogenetic abnormalities such as TP53 and del(5q). When mutational profiles were incorporated into prognostic models, the presence of NRAS, TP53, WT1, and LRP1B mutations were associated with poor prognosis.
Conclusions: This is the first large-scale study on mutational profiles of Korean MDS patients. Korean MDS patients presented with mutations in previously reported MDS-related genes. However, there were significant differences in the mutation distributions which may represent ethnic differences. The molecular profiling of target genes can improve diagnostic accuracy for ICUS and MDS and can assist better subclassification of prognostic groups of MDS patients.