Somatic mutations and their clinical implications in Korean acute myeloid leukemia patients

Abstract

Background Although, the mutational landscape of acute myeloid leukemia (AML) has been revealed by means of next-generation sequencing (NGS), low frequency mutation is yet to be discovered. In the present study, we performed NGS with bone marrow specimens to identify novel oncogenic mutations in AML at various clinical stages.

Materials and Methods We performed whole exome sequencing (WES) of 53 AML samples, followed by targeted resequencing of 389 AML samples. Targeted resequencing was performed for all non-synonymous variants revealed by WES. Samples used for targeted resequencing included samples at diagnosis (n=155), at relapse/persistence (n=63) and at complete remission (n=87). The results were filtered using Exome Aggregation Consortium, 1000 Genome Database, Korean Variant Archive (KOVA) and The Cancer Genome Atlas.

Results We could identify 590 loci that is potentially related to AML with WES. Taregted resequencing of 590 loci revealed 29 loci is recurrently found in AML samples. Mutation frequency of well known oncogenic variants including IDH2 p.R172K, IDH2 p.R140H, NRAS p.G13D, NRAS p.G12D, and DNMT3A p.R693C did not differ from the frequency of TCGA database. Whole Seven variants (PCDHA1 p.L666F, SERAC1 p.R645C, C7orf50 p.H113Y, TRRAP p.S722F, FAM178 p.T105M, GATA2 p.R330L, and PIWIL3 p.N872S) were found to be putative novel oncogenic mutations. Results of an in silico prediction tool suggested that GATA2 p.R330L and TRRAP p.S722F were highly likely to be functional oncogenic mutations. The oncogenic mutation TRRAP p.S722F, which had been described previously in melanoma, was found only in acute promyelocytic leukemia (APL) samples. Sequencing of specimens from an additional 24 patients with APL revealed a frequency of 12.8% for TRRAP p.S722F.

Conclusion We found 7 novel mutations in AML, including GATA2 p.R330L and TRRAP p.S722F, which are putative oncogenic driver. TRRAP p.S722F especially appears to be a partner mutation of the PML-RARα fusion in more than 10% of patients with APL.