Demonstration Of Significant Clonal Evolution From Diagnosis To Relapse In Childhood Aml Determined By Exome Capture Sequencing: An Nci/Cog Target Aml Study

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Acute myeloid leukemia (AML) is a heterogeneous group of disorders with significant genomic complexity that contributes to variable clinical responses and poor outcomes despite intensive therapy. Although genomic alterations, including karyotypic alterations and somatic mutations have been identified in most patients with AML, their utility has been limited by an inability to accurately predict outcome in the majority of patients. There is also little information on the molecular evolution of AML from diagnosis to relapse. To define the genomic profile of relapse in AML and evaluate the extent of clonal evolution from diagnosis to relapse, we performed exome capture sequencing in matched trios of specimens (diagnostic, remission and relapse specimens) from 22 patients with AML (64 specimens) who were treated on COG clinical trials and lacked previously known high risk features. In the 22 matched diagnostic and 20 relapse cases, 729 somatic variants were identified with a variant allelic frequency ranging from 1% to 94% in diagnostic (N=384) or relapse (N=345) specimens (33.1 mutations/patient) of which 372 were verified with secondary deep sequencing of targeted regions. A verification rate of 86% in mutations with >20% variant allelic frequency was achieved. 335 somatic mutations (median15.5 mutations/patient, range 8-42 mutations/patient) were observed in the 20 cases with diagnostic and relapse specimens. Of these 335 somatic mutations, 221 mutations (66%) in 193 genes were identified in the diagnostic specimens, of which 107 mutations (49%) in 101 genes were present at disease recurrence. In addition to the 107 mutations that persisted from diagnosis to relapse, there was emergence of an additional 114 mutations in 106 genes at the time of relapse, possibly due to clonal selection of a rare pre-existing clone. Somatic mutations in 17 genes were detected in more than one patient at either diagnosis or relapse or both. Of the mutations that were present at both diagnosis and relapse, only 2 genes (KIT and TET2) were mutated in more than one patient, highlighting the paucity of common, novel relapse-associated mutations in the studied cohort. In addition evaluation of copy number (CN) alterations by SNP genotyping in the diagnostic and relapse specimens revealed similar clonal evolution with apparent resolution of diagnostic CN variations and appearance of novel somatic CN alterations in relapse specimens. The study results highlight the genomic complexity of childhood AML, and suggest significant clonal evolution from diagnosis to relapse, with resolution of mutations associated with chemotherapy sensitive clones. Newly evolved mutations may represent rare, chemotherapy resistant clones present at diagnosis, which are selected by exposure to chemotherapy, and may cooperate with other mutations to lead to therapy resistance and poor outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-93. doi:1538-7445.AM2012-LB-93