Prevalence & Prognosis Value of TET2 Gene Polymorphisms in Childhood Acute Myeloid Leukemia in Taiwan

Abstract

Abstract 1551 Introduction:Acute myeloid leukemia (AML) is a phenotypically and genetically heterogeneous disease, accounts for 10% of childhood leukemia. The prognosis of children with AML has improved greatly over the past 30 years, and the Taiwan Pediatric Oncology group (TPOG) AML 97A and B protocols had been designed and explored in 1997 for the treatment of AML in Taiwan with complete remission (CR) and overall survival (OS) rates as high as 80–90% and 50–60%. In recent years, molecular research identified an increasing panel of genetic markers in AML, enhancing better risk stratification, modify treatment strategy and improving prognosis. The tet oncogene family member 2 (TET2) gene, a candidate tumor suppressor gene, and the mutations are found in adult AML with prevalence of around 10–20% and is associated to prognosis. However, the report in childhood AML is limited. Here, we assess the prevalence of TET2 gene alterations in childhood AML and to identify its association with prognosis. Method:We enrolled children who were diagnosed AML and visited national Taiwan university hospital between Jan, 1997 to June, 2010. The patients with APL (acute promyeloid leukemia) were excluded due to different treatment protocol. All the children were treated by TPOG AML 97 protocol. The induction therapy consist two courses of cytarabine (Ara-C) and idarubicin (IDR). Patients who achieved CR subsequently received four courses of consolidation therapy consisted of high-dose Ara-C and mitoxantrone or etoposide. The clinical characteristics, such as age, sex, laboratory data, cytogenetics information, relapse, survival time were all collected from TPOG database. DNA was isolated from bone marrow cells at diagnosis and sequence analysis was carried out for TET2 gene. The all data of eligible cases will be collected and analyzed for estimating EFS (event free survival), and OS (overall survival). Survival curves will be estimated by the Kaplan-Meier method. Comparisons were made by Chi-square test for binary variables and t test for continuous variables. For all analyses, the P-values were two-tailed, and a P < 0.05 was considered statistically significant. Results:Total of 56 pediatric AML patients were enrolled. The mean age is 9.07 ± 5.4 (0.01∼17.54) years. There are 34 (60.7%) males. Twenty-four (42.9%) patients had relapse and the overall survival rate is 44.6% (25/56). In this study, there was no nonsense or frameshift mutation, which is frequently identified in adult AML. Total 44 patients (78.6%) present TET2 SNP (single nucleotide polymorphism) and the details are listed in Table 1. There are 18 SNP, and 3 of them (rs72224084, rs58201766, rs59046770) are located in intron. Other 15 SNP are all located in exon. Most of them are located in exon 3 (27 events) and exon 11 (32 events). Only SNP rs3733609 is located in exon 9, and this is synonymous mutation. There are 9 SNP located in exon are not reported in reference yet. Among these, 4 SNP is synonymous mutation. All SNPs are heterozygous, except 4 SNP are homozygous, which are all SNP rs2454206 (I1762V). The clinical characteristics between patients with or without TET2 SNP, including sex, age, white count while diagnosis, chromosome abnormalities, death and relapse are not different between this 2 groups. Kaplan–Meier survival analysis is used to test the correlation between TET2 gene polymorphism to prognosis, including overall survival and event free survival. There was no difference.Table 1TET2 gene alterations in childhood AML. (n=56)RegiondbSNP rs# cluster idcDNA position & SNP alleleAmino acid position & protein residuePatient numberintronrs72224084-/AGATAGAT2rs58201766-/ATGATAGA25rs59046770-/TAGA12Exon 3rs12498609149 C→GP29R2rs6843141715 G→AV218M8983 T→CL307P11485 G→AP474P11889 C→GS609C12667 T→GF868L42503 C→TR814C1rs37969273180 G→AS1039S8rs1116786783179 C→TS1039L1Exon 9rs37336094193 T->CH1380H3Exon 114601 A→GE1513G2rs24542065347 A→GI1762V275502 A→GQ1813Q15387 G→AS1765N15657 C→GA1865G1 Conclusion:As we know, we are the first group to publish TET2 gene alterations in childhood AML in Asian. We conclude the prevalence of TET2 mutations in pediatric AML patients is far lower than in adults and the TET2 polymorphisms are not associated with prognosis. Disclosures:No relevant conflicts of interest to declare.