Abstract
Decitabine is a hypomethylating agent with proven clinical efficacy in myelodysplastic syndrome (MDS). The current study analyzed the role of single nucleotide polymorphism array (SNP-A)-based karyotyping in prediction of clinical outcome in MDS or chronic myelomonocytic leukemia (CMML) patients following decitabine therapy. A total of 61 MDS/CMML patients treated with decitabine were evaluated with Genome-Wide Human SNP 6.0 Array using DNAs derived from marrow samples. The primary endpoint was the best response rate including complete (CR) and partial response (PR) with overall (OS) and event-free survival (EFS) as secondary endpoints. Best response was noted in 14 patients (26.4 %) out of 53 evaluated patients including 12 CR and two PR with median follow-up of 21.6 months. A total of 81 abnormal SNP lesions were found in 25 out of 61 patients (41.0 %). The patients carrying abnormal SNP lesions showed an inferior CR/PR rate (p = 0.002) and showed a trend of worse OS (p = 0.02 in univariate, p = 0.09 in multivariate) compared to those without SNP lesions, but not were associated with inferior EFS. The presence of abnormal SNP lesions in MDS was associated with adverse outcomes following decitabine therapy. Further study is strongly warranted to establish the role of SNP-A karyotyping in MDS.
Similar content being viewed by others
References
Greenberg PL, Attar E, Battiwalla M et al (2008) Myelodysplastic syndromes. J Natl Compr Canc Netw 6:902–926
Rollison DE, Howlader N, Smith MT et al (2008) Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 112:45–52
Kantarjian H, Oki Y, Garcia-Manero G et al (2007) Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109:52–57
Lyons RM, Cosgriff TM, Modi SS et al (2009) Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 27:1850–1856
Silverman LR, Demakos EP, Peterson BL et al (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20:2429–2440
Steensma DP, Baer MR, Slack JL et al (2009) Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol 27:3842–3848
Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088
Germing U, Gattermann N, Strupp C, Aivado M, Aul C (2000) Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res 24:983–992
Vardiman JW (2006) Hematopathological concepts and controversies in the diagnosis and classification of myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program 2006:199–204
Faderl S, Kantarjian HM (2004) Novel therapies for myelodysplastic syndromes. Cancer 101:226–241
Pozdnyakova O, Miron PM, Tang G et al (2008) Cytogenetic abnormalities in a series of 1,029 patients with primary myelodysplastic syndromes: a report from the US with a focus on some undefined single chromosomal abnormalities. Cancer 113:3331–3340
Haase D, Germing U, Schanz J et al (2007) New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110:4385–4395
Barresi V, Romano A, Musso N et al (2007) Broad copy neutral-loss of heterozygosity regions and rare recurring copy number abnormalities in normal karyotype-acute myeloid leukemia genomes. Genes Chromosomes Cancer 49:1014–1023
Bullinger L, Kronke J, Schon C et al (2010) Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis. Leukemia 24:438–449
Nomdedeu JF, Perea G, Estivill C et al (2004) Loss of heterozygosity of the polymorphic PIG3 microsatellite with low frequency in de novo acute myeloid leukemias. Leukemia 18:1148–1149
Huh J, Jung CW, Kim HJ et al (2012) Different characteristics identified by single nucleotide polymorphism array analysis in leukemia suggest the need for different application strategies depending on disease category. Genes Chromosomes Cancer 52:44–55
Huh J, Kim HJ, Jung CW et al (2012) A genome-wide single-nucleotide polymorphism-array can improve the prognostic stratification of the core binding factor acute myeloid leukemia. Am J Hematol 87:961–968
Yi JH, Huh J, Kim HJ et al (2011) Adverse prognostic impact of abnormal lesions detected by genome-wide single nucleotide polymorphism array-based karyotyping analysis in acute myeloid leukemia with normal karyotype. J Clin Oncol 29:4702–4708
Miller BJ, Wang D, Krahe R, Wright FA (2003) Pooled analysis of loss of heterozygosity in breast cancer: a genome scan provides comparative evidence for multiple tumor suppressors and identifies novel candidate regions. Am J Hum Genet 73:748–767
Saeki H, Kitao H, Yoshinaga K et al (2011) Copy-neutral loss of heterozygosity at the p53 locus in carcinogenesis of esophageal squamous cell carcinomas associated with p53 mutations. Clin Cancer Res 17:1731–1740
Mohamedali A, Gaken J, Twine NA et al (2007) Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes. Blood 110:3365–3373
Tiu RV, Gondek LP, O’Keefe CL et al (2011) Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 117:4552–4560
Langemeijer SM, Kuiper RP, Berends M et al (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41:838–842
Itzykson R, Kosmider O, Cluzeau T et al (2010) Presence of TET2 mutation predicts a higher response rate to azacitidine in MDS and AML Post MDS. Blood 116:Abstract 439
Nikoloski G, Langemeijer SM, Kuiper RP et al (2010) Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 42:665–667
Kulasekararaj AG, Mohamedali AM, Smith AE et al (2010) Polycomb complex group gene mutations and their prognostic relevance in 5-azacitidine treated myelodysplastic syndrome patients. Blood 116:Abstract 125
Xu F, Li X, Wu L et al (2010) Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring. Ann Hematol 90:643–653
Christiansen DH, Andersen MK, Pedersen-Bjergaard J (2001) Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol 19:1405–1413
Swerdlow S, Campo E, Harris NL et al (2008) WHO classification of tumours of haematopoietic and lymphoid tissue (IARC WHO classification of tumours), 4th ed. WHO, Geneva
Shaffer LG, Slovak ML, Campbell LJ (2009) An international system for human cytogenetic nomenclature. Karger, Basel
Cheson BD, Greenberg PL, Bennett JM et al (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108:419–425
Gondek LP, Tiu R, O’Keefe CL, Sekeres MA, Theil KS, Maciejewski JP (2008) Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood 111:1534–1542
Makishima H, Rataul M, Gondek LP et al (2010) FISH and SNP-A karyotyping in myelodysplastic syndromes: improving cytogenetic detection of del(5q), monosomy 7, del(7q), trisomy 8 and del(20q). Leuk Res 34:447–453
Jasek M, Gondek LP, Bejanyan N et al (2010) TP53 mutations in myeloid malignancies are either homozygous or hemizygous due to copy number-neutral loss of heterozygosity or deletion of 17p. Leukemia 24:216–219
Acknowledgments
This study was supported by grants of Korea Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A090618 and A100821) and a grant of the National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea (A111218-GM06).
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplemental Table 1
Summary of abnormal SNP lesions identified by genome-wide SNP array-based karyotyping (DOCX 36 kb)
Supplemental Table 2
Summary of abnormal SNP lesions in individual cases with normal karyotype by metaphase analysis (DOC 58 kb)
Supplemental Figure 1
Result of metaphase cytogenetics and SNP-A karyotyping (A, metaphase cytogenetics; B, SNP-A karyotyping; C, combined (any abnormality detected by either method was considered as abnormal) (no. of patients, percent) (DOC 63 kb)
Rights and permissions
About this article
Cite this article
Yi, J.H., Huh, J., Kim, HJ. et al. Genome-wide single-nucleotide polymorphism array-based karyotyping in myelodysplastic syndrome and chronic myelomonocytic leukemia and its impact on treatment outcomes following decitabine treatment. Ann Hematol 92, 459–469 (2013). https://doi.org/10.1007/s00277-012-1635-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-012-1635-7