ABSTRACT: Acquired somatic mutations are crucial for the development of the majority of cancers. We performed a comprehensive comparative analysis of the mutational landscapes and their correlation to CHIP-related (clonal hematopoiesis of indeterminate potential) mutations and patient age of 122 genes in 3096 cases with 28 different hematological malignancies. Differences were observed regarding (i) the median number of mutations (highest, median n=4: aCML, CMML, MDS/MPN-U, s-AML; lowest, n=0, CML, MLN-eo, MGUS, PPBL), (ii) specificity of certain mutations (high frequencies in e.g. aCML (ASXL1, 86%), FL (KMT2D, 87%; CREBBP, 73%), HCL (BRAF, 100%), LPL (MYD88, 98%; CXCR4, 51%), MPN (JAK2, 68%)), (iii) distribution of mutations (broad distribution within/across the myeloid/lymphoid lineage e.g. for TET2, ASXL1, DNMT3A, TP53, BCOR, ETV6), (iv) correlation of mutations to patient age (correlated to older age across entites: e.g. TET2, DNMT3A, ASXL1, TP53, EZH2, BCOR, GATA2, IDH2; younger age: e.g. KIT, POT1, RAD21, U2AF2; WT1), (v) correlation of mutation number per patient with age (total cohort (p<0.001), AML (p<0.001), B-ALL (p=0.015), CLL (0.039), MDS (p<0.001), MPN (p<0.001), T-ALL (p=0.005)). Moreover, we observed high frequencies of mutations in RUNX1, SRSF2, IDH2, NRAS, EZH2 in cases comprising at least one DTA mutation (DNMT3A, TET2, ASXL1), while in cases without DTA mutations TP53, KRAS, WT1, SF3B1 were more frequent across entities, suggesting differences in pathophysiology. These results give further insight into the complex genetic landscape and the role of DTA mutations in hematological neoplasms and define mutation-driven entities (MDS/MPN overlap, s-AML) in comparison to entities defined by chromosomal fusions (CML, MLN-eo).
