Effect of mutation allele frequency on the risk stratification of myelodysplastic syndrome patients

Abstract

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal myeloid malignancies. Though several recurrent mutations are closely correlated with clinical outcomes, data concerning the association between mutation variant allele frequencies (VAF) and prognosis are limited. In this study, we performed comprehensive VAF analyses of relevant myeloid-malignancy related mutations in 698 MDS patients and correlated the results with their prognosis. Mutation VAF in DNMT3A, TET2, ASXL1, EZH2, SETBP1, BCOR, SFSF2, ZRSR2, and TP53 mutations correlated with outcomes.In multivariable analysis, DNMT3A and ZRSR2 mutations with high VAF and mutant IDH2, CBL, U2AF1, and TP53 were independent poor prognostic factors for overall survival. A substantial portion of patients in each revised International Prognostic Scoring System (IPSS-R) risk group could be adjusted to different prognostic groups based on the integrated VAF and mutational profiles. Patients with these unfavorable mutations in each IPSS-R risk subgroup had survivals worse than other patients of the same risk but similar to those in the next higher-risk subgroup. Furthermore, patients harboring U2AF1 mutation might benefit from hypomethylating agents. This study demonstrated the critical role of VAF of mutations for risk stratification in MDS patients and may be incorporated in novel scoring systems.

Clinico‐genetic and prognostic analyses of 716 patients with primary myelodysplastic syndrome and myelodysplastic syndrome/acute myeloid leukemia based on the 2022 International Consensus Classification

“…The algorithm for variant analysis using diagnostic samples was established in an earlier study. 20 We verified the gene sequencing results of CEBPA mutations and FLT3-ITD using Sanger sequencing due to sensitivity issues.…”

“…Cytogenetic analyses were performed and interpreted according to the International System for Human Cytogenomic Nomenclature 16,17 . The TruSight myeloid sequencing panel (Illumina, San Diego, CA, USA), and HiSeq 2500 system (Illumina) was used to analyze the gene alterations in 54 genes associated with myeloid‐neoplasms (Table S1), as described previously 18–20 . Library preparation and sequencing were performed according to the manufacturer's instructions.…”

“…We used the catalog of somatic mutations in cancer (version 86) and single nucleotide polymorphism (version 151) databases, ClinVar, PolyPhen‐2, and sorting intolerant from tolerant tool to perform genomic sequencing of each variant. The algorithm for variant analysis using diagnostic samples was established in an earlier study 20 . We verified the gene sequencing results of CEBPA mutations and FLT3 ‐ITD using Sanger sequencing due to sensitivity issues.…”

“…16,17 The TruSight myeloid sequencing panel (Illumina, San Diego, CA, USA), and HiSeq 2500 system (Illumina) was used to analyze the gene alterations in 54 genes associated with myeloid-neoplasms (Table S1), as described previously. [18][19][20] Library preparation and sequencing were performed according to the manufacturer's instructions. The median reading depth was 10 550x.…”

Validation of the Molecular International Prognostic Scoring System in Patients with Myelodysplastic Syndromes Defined by International Consensus Classification

“…Cytogenetic analyses were performed and interpreted based on the International System for Human Cytogenetic Nomenclature (19,20). TruSight myeloid sequencing panel (Illumina, San Diego, CS, USA) and the HiSeq platform (Illumina, San Diego, CA, USA) were used to analyze the alterations of 54 myeloidneoplasm relevant genes (21) (Supplemental Table 1), as previously described (22,23). Five residual genes (ETNK1, GNB1, NF1, PPM1D, and PRPF8), de ned using the IPSS-M model, were not included.…”