PB2072 GENETIC MUTATION IN CYTOPENIC PATIENTS: DISTINCTIVE GENOMIC PROFILE BETWEEN PRECLINICAL VS. CLINICAL MYELODYSPLASTIC SYNDROME

Abstract

Background: Myelodysplastic syndromes (MDS) are heterogeneous groups of clonal hematopoietic disorders. Diagnostic criteria of MDS is mainly based on morphologic assessment which remains a major diagnostic challenge due to individual variability among hematologists. Genetic mutations were identified in myelodysplastic syndrome but also found in cytopenic patients without dysplasia or non-significant dysplasia (preclinical MDS). Clinical utilities of genetic mutations were not clearly understood in preclinical MDS. We aimed to explore clinical implications of genetic mutations in preclinical MDS and compare with myelodysplastic syndromes. Secondary objective was to find association between degree of dysplasia and somatic mutations. Aims: We aimed to explore clinical implications of genetic mutations in preclinical MDS and compare with myelodysplastic syndromes. Secondary objective was to find association between degree of dysplasia and somatic mutations. Methods We enrolled patients with peripheral cytopenia ≥1 lineage (ANC < 1,800/mm3, hemoglobin < 10 gm/dL, platelet < 100 × 109/mL) with no other explainable causes of cytopenia. Bone marrow examinations were evaluated independently by 2 hematologists. If there were discrepant interpretations, cases would be reviewed by the third hematologist for final consensus. Bone marrow aspirations were evaluated as non-diagnostic marrow or dysplastic marrow using dysplasia cut-off of 10%. We extracted DNA from bone marrow and performed targeted sequencing by next generation sequencing (NGS) encompassing 143-gene panels. Results: Thirty-three patients were enrolled in this study. The median age at diagnosis was 71 years. Results of bone marrow examinations were categorized by morphology into 4 group, no dysplasia 15.1%, non-significant dysplasia (dysplasia < 10%) 9%, low risk MDS (IPSS-R ≤3.5) 51.5% and high-risk MDS (IPSS-R >3.5) 24.2%. Twenty-five from 33 cases (75.7%) harbored more than 1 somatic mutation. Twenty-six gene mutations were identified. Mutations were detected 2.18 mutation per 1 patient in average. Most frequent somatic mutations were TET2:9 (12.6%), ASXL1:6 (8.4%), TP53:6 (8.4%), RUNX1:6 (8.4%) and DNMT3A:5 (7%). The proportions of cases with somatic mutations were not different across the groups (no dysplasia 80%, non-significant dysplasia 100% and significant dysplasia 72%). According to mutation types in each group, mutations in epigenetic pathways were the most frequent mutations across all patient subgroups (preclinical 53%, low-risk MDS 38%, high-risk MDS 41%). Mutations in signaling pathway were predominated in preclinical MDS group 20% (no dysplasia and non-significant dysplasia) compare to MDS group (5% and 6% in low-risk and high-risk MDS, respectively) whereas mutations in transcription factor were predominated in MDS groups (33% and 29% in low-risk and high-risk MDS, respectively)compared to preclinical MDS group (7%). There was no difference between individual average frequency of gene mutations according to dysplasia subtype (P = 0.276). Higher variant allele frequency (VAF) of mutated genes was significantly observed in high risk MDS (45.3%) compared to low risk MDS (32%) and preclinical MDS (27.4%) (p = 0.003).Summary/Conclusion: In conclusion, molecular profiling was significantly different between preclinical MDS and MDS groups in terms of types of somatic mutations and VAF. This unique contrast could be used to distinguish between preclinical MDS and clinically significant MDS. In contrast, degree of marrow dysplasia was not associated with number of gene mutations in this study.