A novel hierarchical prognostic model of AML solely based on molecular mutations by Vera Grossmann, Susanne Schnittger, Alexander Kohlmann, Christiane.

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A novel hierarchical prognostic model of AML solely based on molecular mutations by Vera Grossmann, Susanne Schnittger, Alexander Kohlmann, Christiane Eder, Andreas Roller, Frank Dicker, Christoph Schmid, Clemens-Martin Wendtner, Peter Staib, Hubert Serve, Karl-Anton Kreuzer, Wolfgang Kern, Torsten Haferlach, and Claudia Haferlach Blood Volume 120(15):2963-2972 October 11, 2012 ©2012 by American Society of Hematology

TP53 mutations: localization and association with cytogenetics and other molecular mutations. TP53 mutations: localization and association with cytogenetics and other molecular mutations. (A) Molecular mutations in TP53. The numbers of mutations are reflected by the numbers of colored dots which also indicate the mutation effect on the amino acid level. (B) Association between TP53 mutations and karyotype. The Circos plot illustrates the association between TP53 mutations and cytogenetic subgroups. The width of the arches indicates the percentage of positive samples. (C) Mutational complexity of TP53 mutations. The Circos diagram shows the mutational events in patients with TP53 mutations and a respective second molecular mutation. The length of the gene section indicates the number of obtained mutations per marker. The width of the arches indicates the percentage of mutated samples. Vera Grossmann et al. Blood 2012;120:2963-2972 ©2012 by American Society of Hematology

Mutation pattern of AML cases with intermediate and unfavorable cytogenetics. Mutation pattern of AML cases with intermediate and unfavorable cytogenetics. Distributions and frequencies are given for aberrations in TP53, NPM1, CEBPA, MLL-PTD, ASXL1, RUNX1, and FLT3-ITD. The patient cohort is further annotated according to cytogenetics. Cases with favorable risk cytogenetics were not included, as not all molecular markers were analyzed in all cases of this subset because the hierarchical model prognostic assignment was based on the detection of the specific fusion transcript irrespective of further mutations. Vera Grossmann et al. Blood 2012;120:2963-2972 ©2012 by American Society of Hematology

Model based on molecular mutations. Model based on molecular mutations. (A) Categorization of all mutations detected in AML to 5 prognostic groups. The cohort was stratified according to an “entity-based” hierarchy: (1) PML-RARA, CEBPA double-mutated (n = 71); (2) RUNX1-RUNX1T1, CBFB-MYH11, NPM1mut/FLT3-ITD− (n = 252); (3) CEBPA single-mutated, NPM1mut/FLT3-ITD+, FLT3-ITD+, wild-type cases (n = 235); (4) MLL-PTD and/or RUNX1mut and/or ASXL1mut (n = 203); (5) TP53 mutations (n = 80). (B-C) Kaplan-Meier plots for the molecular mutation-based model, which separates patients into 5 prognostic subgroups: (1) PML-RARA, CEBPA double-mutated (n = 71); (2) RUNX1-RUNX1T1, CBFB-MYH11, NPM1mut/FLT3-ITD− (n = 252); (3) CEBPA single-mutated NPM1mut/FLT3-ITD+, FLT3-ITD+, wild-type cases (n = 235); (4) MLL-PTD and/or RUNX1 and/or ASXL1 (n = 203); (5) TP53 mutations (n = 80). (B) OS (P values between the subgroups are 1 vs 2, P = .004; 2 vs 3, P = .001; 3 vs 4, P = .001; 4 vs 5, P < .001, respectively). (C) EFS (P values between the subgroups are 1 vs 2, P = .001; 2 vs 3, P = .011; 3 vs 4, P = .004; 4 vs 5, P < .001, respectively). (D-E) Comparison of cytogentic and molecular genetic model. Cohort subdivided according to (D) cytogenetics and (E) molecular mutations. The model based on molecular mutations leads to 5 prognostic subsets instead of 3 in the cytogenetic model and thus a refined assignment of patients to distinct prognostic groups with large differences in outcome. Vera Grossmann et al. Blood 2012;120:2963-2972 ©2012 by American Society of Hematology