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Mutation in TET2 or TP53 predicts poor survival in patients with myelodysplastic syndrome receiving hypomethylating treatment or stem cell transplantation

Bone Marrow Transplantation volume 50, pages 1132–1134 (2015)Cite this article

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Recent molecular studies identified genetic mutations in myelodysplastic syndrome (MDS) and their associations with clinical parameters.1, 2 As an increasing number of recurrent somatic mutations have been found, many investigators are focusing on genetic mutations as candidate molecular markers for MDS prognosis and treatment outcomes, especially following hypomethylating treatment (HMT) or stem cell transplantation (SCT). In this study, we analyzed recurrent TET2, TP53, ETV6, RUNX1, EZH2, ASXL1, SF3B1, U2AF1 and SRSF2 mutations, which are relatively frequent, and their influence on survival was reported independently of clinical parameters.2, 3 Fifty-two patients receiving HMT and/or SCT for MDS at our institution from April 2009 to May 2011 were retrospectively analyzed. Median age of the patients was 52 years (range, 18–73 years), and 36 (69.1%) patients were male. Clinical and disease characteristics are summarized in Table 1. Treatment strategies followed the institution’s guideline elsewhere reported,4 and initial treatment was with HMA in 43 patients, SCT in 8 patients and intensive chemotherapy in 1 patient. SCT was immediately planned whenever possible for patients with the higher-risk (Hr, intermediate-2/high by international prognostic scoring system) group, but planned for the lower-risk (Lr, low/intermediate-1 by international prognostic scoring system) group with life-threatening cytopenia or HMT failure.5, 6 Forty-three patients received a median of four cycles (range, 1–29) of azacitidine (n=24) or a median of two cycles (range, 1–5) of decitabine (n=19), and responses were assessed using standard criteria.7 Forty patients received PBSCT after conditioning with fludarabine (150 mg/m2), IV busulfan (12.8 or 6.4 mg/kg) and rabbit ATG (5 or 10 mg/kg). Fractionated total-body irradiation (800 cGy) was added for haploidentical SCT. Mutation analyses were performed using bone marrow genomic DNAs. Mutations in nine genes were evaluated by Sanger sequencing using the ABI PRISM 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA) using primers designed with Primer 3 (Supplementary Table 1). SF3B1, U2AF1 and SRSF2 mutational data reported previously were used.8

Table 1 Patient characteristics at the time of treatment
Full size table

Thirty-three patients (63.5%) had mutations in one or more genes (Supplementary Table 2). ASXL1 was the most frequently mutated gene (n=13, 25.0%), followed by U2AF1 (n=11, 21.2%), TET2 (n=8, 15.4%), RUNX1 (n=7, 13.5%), SRSF2 (n=5, 9.6%), EZH2 (n=4, 7.7%), TP53 (n=4, 7.7%), SF3B1 (n=3, 5.8%) and ETV6 (n=2, 3.8%). Eighteen patients (57.6%) had more than two genetic mutations; 4 patients (15.2%) had mutations in three genes; 14 patients (42.4%) had mutations in two genes; and 14 patients (42.4%) had mutations in one gene. Thirty patients (57.7%) revealed abnormal karyotype and 56.7% (17/30) of them demonstrated genetic mutations. Sixteen patients with normal karyotype (72.7%, 16/22) had genetic mutations. Therefore, 88.5% (46/52) of the enrolled MDS patients were accompanied with genetic aberrations.

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Acknowledgements

This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120175) and was partly sponsored by a research fund from Kyowa Hakko Kirin Korea.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea,

    M Kim, A Kwon & J Park

  2. Catholic Blood and Marrow Transplantation Center, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea,

    S-A Yahng, Y-W Jeon, J-H Yoon, S-H Shin, S-E Lee, B-S Cho, K-S Eom, S Lee, C-K Min, H-J Kim, S-G Cho, D-W Kim, J-W Lee, W-S Min & Y-J Kim

  3. Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea,

    S-H Lee

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Kim, M., Yahng, SA., Kwon, A. et al. Mutation in TET2 or TP53 predicts poor survival in patients with myelodysplastic syndrome receiving hypomethylating treatment or stem cell transplantation. Bone Marrow Transplant 50, 1132–1134 (2015). https://doi.org/10.1038/bmt.2015.110

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