1. Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy
- Author
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François Delhommeau, Ramy Rahmé, Nicolas Boissel, Pierre Sujobert, Marie Sebert, Emmanuelle Clappier, Raphael Itzykson, Anna Raimbault, Matthieu Duchmann, Samuel Quentin, Nathalie Dhedin, Florence Rabian, Xavier Thomas, Jean Soulier, Odile Maarek, Etienne Lengliné, Emmanuel Raffoux, Loic Vasseur, Pierre Fenaux, Rathana Kim, Marco Cerrano, Marie Passet, Justine Pasanisi, Lionel Ades, Hervé Dombret, Pierre Hirsch, and Karine Celli-Lebras
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,Prognostic factor ,Chemotherapy ,medicine.medical_specialty ,medicine.medical_treatment ,Myeloid leukemia ,Hematology ,Biology ,Phenotype ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,medicine ,Genotyping ,Exome sequencing ,Dominance (genetics) - Abstract
Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ = 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P = 0.028) and a lower Shannon Index (HR = 0.68, P = 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P = 1 × 10−5, Shannon Index HR = 0.81, P = 0.007). By re-interrogating paired diagnosis/relapse exomes from 50 cytogenetically normal AMLs, we find clonal dominance at diagnosis to be correlated with the gain of a significantly higher number of mutations at relapse (P = 6 × 10−6), hence with clonal sweeping. Our results suggest that clonal dominance at diagnosis is associated with the presence of a leukemic phenotype allowing rapid expansion of new clones and driving relapse after chemotherapy.
- Published
- 2020
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