ena-STUDY-UNIVERSITY OF TORONTO-11-04-2018-12:04:15:794-107
Longitudinal mutational analyses integrated with fusion transcript level in core binding factor acute myeloid leukemia
Core-binding factor acute myeloid leukemia (CBF-AML) consists of two subtypes with cytogenetic abnormalities, t(8;21)/RUNX1-RUNX1T1 and inv(16)/CBFB-MYH11. Although their mutational landscapes at diagnosis are relatively well-studied, mutational dynamics in CBF-AML has not been elucidated using serial samples. Here, we sequenced 357 samples from 87 CBF-AML patients collected at serial time-points. Consistent with previous studies, mutation patterns were distinct between t(8;21) and inv(16) AML. In survival analyses, KIT-D816mut and RASmut were identified as prognostic factors. More importantly, we investigated dynamics of allelic burden from diagnosis to complete remission (CR) and to relapse and its clinically relevance. First, we show that majority of allelic burden was cleared although residual allelic burden was common at CR. However, residual allelic burden of targeted somatic mutations at CR was not able to distinguish relapsed patients from non-relapsed patients. Furthermore, systematic comparison between initial and relapse AML clones revealed significant changes in subclonal architecture in most patients. Overall, clinical interpretation of residual allelic burden at CR requires special attention and needs to correlate with dynamics of fusion gene transcript level in CBF-AML.
Core-binding factor acute myeloid leukemia (CBF-AML) consists of two subtypes with cytogenetic abnormalities, t(8;21)/RUNX1-RUNX1T1 and inv(16)/CBFB-MYH11. Although their mutational landscapes at diagnosis are relatively well-studied, mutational dynamics in CBF-AML has not been elucidated using serial samples. Here, we sequenced 357 samples from 87 CBF-AML patients collected at serial time-points. Consistent with previous studies, mutation patterns were distinct between t(8;21) and inv(16) AML. In survival analyses, KIT-D816mut and RASmut were identified as prognostic factors. More importantly, we investigated dynamics of allelic burden from diagnosis to complete remission (CR) and to relapse and its clinically relevance. First, we show that majority of allelic burden was cleared although residual allelic burden was common at CR. However, residual allelic burden of targeted somatic mutations at CR was not able to distinguish relapsed patients from non-relapsed patients. Furthermore, systematic comparison between initial and relapse AML clones revealed significant changes in subclonal architecture in most patients. Overall, clinical interpretation of residual allelic burden at CR requires special attention and needs to correlate with dynamics of fusion gene transcript level in CBF-AML.