U2AF1 mutation in de novo myelodysplastic syndromes (MDS) and its genetic evolution profile of secondary acute myeloid leukemia (sAML): a comparative analysis of 68 paired matched samples

Abstract

214 U2AF1 mutation in de novo myelodysplastic syndromes (MDS) and its genetic evolution profile of secondary acute myeloid leukemia (sAML): a comparative analysis of 68 paired matched samples Che-Wei Ou, Ming-Chung Kuo, Tung-Huei Lin, Yu-Shu Shih, Po Dunn, Tung-Liang Lin, Po-Nan Wang, Jin-Hou Wu, Chen-Yu Lai, Der-Cherng Liang and Lee-Yung Shih Chang Gung Memorial Hospital, Chang Gung University and Mackay Memorial Hospital, Taiwan Objectives: We aimed to investigate (1) the clinical relevance of U2AF1 gene mutation and its co-existing mutations in MDS, and (2) the genetic evolution profile of co-existing mutations in sAML transformation from MDS. Materials and Methods: Mutational analysis of U2AF1 (exons 2 and 6) was performed in 68 paired MDS/sAML bone marrow samples and in non-paired diagnosis samples in another 80 cases with de novo MDS. Additional 24 mutated genes were also analyzed at both MDS and sAML phases in U2AF1-mutated patients by using PCR-based assays followed by direct sequencing. The allelic burden of mutated genes was measured by pyrosequencing. Results: Twenty of 148 MDS patients (13.6%) had U2AF1 mutations (12 Ser34Phe, 3 Ser34Tyr, and 5 Gln157Pro). Co-existing mutations of U2AF1 with epigenetic regulators occurred in 10 patients (4 ASXL, two each for DNMT3A, TET2, and EZH2). U2AF1 mutation was significantly associated with younger age (P=0.032). There was no correlation between U2AF1 mutation status and gender, blood counts, cytogenetics, or IPSS-R risk groups whereas RAEB-2 was associated with a lower frequency of U2AF1 mutation (P=0.049). U2AF1 mutation had no impact on risk of sAML transformation (P=0.807), sAML-free survival (P=0.998) or overall survival (P=0.516). Of the 68 paired MDS/sAML samples, 12 had U2AF1 mutations at both phases and none acquired or lost U2AF1 mutation during sAML progression. There was no difference in the U2AF1 mutant allelic burden between MDS and sAML phases (P=0.165). In the 6 patients also carrying epigenetic regulator mutations, the mutation status and mutant levels remained stable in both MDS/sAML phases. In U2AF1-mutated patients, progression to sAML was accompanied by evolution of new mutant clones (2 RUNX1 and one each for PTPN11 and CBL) or clonal expansion of a pre-existing subclones (one each for NRAS and RUNX1). Conclusions: Our results showed that mutations of epigenetic regulators occurred in half of U2AF1-mutated patients. The two mutations remained no changes in sAML transformation whereas acquisition of additional genetic alterations or expansion of small pre-existing subclones was detected in a subset of U2AF1-mutated patients. Grant support: NHRI-EX103-10003NI, DOH-102-TD-C-111-006, MMHE-101-09 and OMRPG3C0021, Taiwan.