TET2 SNP rs2454206 (I1762V) Correlates with Improved Survival In Pediatric Acute Myelogenous Leukemia, a Report From the Children's Oncology Group

Abstract 949

Deletions and rearrangements involving chromosome 4q24 in patients with myelodysplastic syndrome led to the discovery that the TET2 gene found in this genomic region may contribute to myeloid leukemogenesis. Mutations in this gene were identified in AML that correlated with clinical outcome. We screened genomic DNA extracted from diagnostic specimens of a cohort of 169 pediatric de novo AML patients treated on the Children's Cancer Group study CCG-2961 for genomic alterations in the TET2 gene. Twenty one primer pairs were used to amplify and sequence the entire coding sequence (11 exons) as well as flanking promoter and non-coding regions of TET2. We identified 10 different previously annotated single nucleotide polymorphisms (SNPs) with prevalence greater than 4% in addition to 12 disease associated mutations. Presence of each SNP as well as the mutations as a group were correlated with disease characteristics and clinical outcome.

Of the 10 SNPs evaluated, one SNP correlated significantly with outcome. The minor allele of SNP rs2454206 (I1762V) was found in 54% of samples tested. There was no significant difference in the age or gender of patients with or without SNP rs2454206. The prevalence of SNP rs2454206 varied in different ethnic groups. Of the 92 patients with SNP rs2454206, 85% were Caucasian and 3% were African American compared to 56% and 15% of those without the SNP, respectively (p<0.001 and p=0.018). Conversely, 65% of all Caucasian patients and 21% of all African American patients with AML had SNP rs2454206, similar to the reported SNP frequency in general Caucasian and African American populations. There was no significant difference in presenting white blood cell count, blast percentage or FAB group in patients with and without SNP rs2454206. The prevalence of specific cytogenetic groups and mutations of FLT3/ITD, CEBPA and WT1 did not differ between the groups. There was a lower prevalence of NPM mutation in the SNP rs2454206 group compared to the SNP negative group (2.5% vs. 12.7%, p= 0.035). Patients with SNP rs2454206 were more likely to achieve a complete remission than those without the SNP (80% vs. 63%, p=0.028). Actuarial overall survival at 5 years from diagnosis for patients with SNP rs2454206 was 61±11% vs. 36±12% for those without the SNP (p=0.007). Corresponding event-free survival was 41±12% vs. 27±11% for those with and without the SNP (p=0.051). Of those who achieved a complete remission, overall survival from CR for those with and without SNP rs2454206 was 66% and 43%, respectively (p=0.022). Improved outcome may in part be due to lower treatment related mortality (TRM) where those with SNP rs2454206 had a lower rate of TRM 6±5% vs. 17±9% (p=0.043).

We further evaluated the clinical implications of TET2 mutations. Disease associated mutations of the TET2 gene were identified in 11 patients with 9 heterozygous missense mutations (K423R, N767D, R814H, E1010D, S1039L, A1443V, V1718L, H1817N and E1973K), 2 heterozygous nonsense mutations (Q958X and E1323X) and one heterozygous single base insertion (ins1870-1871) which caused a frame shift beginning with T624N and causing an early termination codon (E637X). Each mutation was found in a single patient sample except for V1718L which was found in two samples. Also, one patient sample had two missense mutations (E1010D and E1973K) and another patient sample contained both nonsense mutations. Therefore a total of 11 out of 169 samples (6.5%) had a TET2 mutation. Of the TET2 mutant patients with available cytogenetics, 50% had t(8;21) compared to 14% of those without a mutation (p=0.026), and there was not an association of TET2 mutation with high risk cytogenetic features. Of the 11 patients with TET2 mutations, 6 patients failed to achieve a complete remission with a CR rate of 45% compared to that of 74% for those without a mutation (p=0.074). Patients with a TET2 mutation had a disease-free survival of 26±31% vs. 42±10% for those without the mutation (p=0.247).

This study demonstrates the potential significance of genomic alterations of the TET2 gene in childhood AML. Further evaluation of TET2 mutations and the SNP rs2454206 in a larger cohort of pediatric AML patients is in process in order to determine if these will be useful markers for risk based stratification and allocation of therapy. The TET2 SNP rs2454206 may represent a new marker of favorable disease in pediatric AML as it does not overlap with other favorable prognostic markers.