Mutational Patterns and Correlation to Chip-Related Mutations in Hematological Malignancies - a Study on Mutation Frequencies of 122 Genes in 28 Entities Including 3096 Cases

Background: Acquired somatic mutations are crucial for the development of the majority of cancers. In hematological malignancies, some molecular mutations are very specific for certain entities (e.g. BRAF in HCL, MYD88 in LPL), while others were detected in a variety of malignancies (e.g. mutations in TP53, TET2, DNMT3A, RUNX1). Moreover, mutations in genes related to CHIP (clonal haematopoiesis of indeterminate potential; ASXL1, TET2, DNMT3A) were detected in an age-related manner. Aim: (1) Analysis/comparison of mutation frequencies of 122 selected genes in 3096 cases with 28 different hematological malignancies for identification of “mutation-driven” entities. (2) Correlation of CHIP-related mutations with mutational landscapes. Methods: Whole-genome sequencing (WGS) was performed for all 3096 patients. For this, 151bp paired-end reads were generated on NovaSeq 6000 and HiSeqX machines (Illumina, San Diego, CA). The Illumina tumor/unmatched normal workflow was used for variant calling. All reported p-values are two-sided and were considered significant at p 50%) comprised: aCML (ASXL1, 86%), BPDCN (TET2, 67%), BL (TP53, 60%), CMML (TET2, 67%; ASXL1, 58%), FL (KMT2D, 87% and CREBBP, 73%), HCL (BRAF, 100%), LPL (MYD88, 98%; CXCR4, 51%), MDS/MPN-U (ASXL1, 60%), MPN (JAK2, 68%), B-NHL (TP53, 50%) and T-NHL (STAT3, 52%). Mutations enriched in distinct entities included SETBP1 (26% in MDS/MPN overlaps), CSF3R (30% in MDS/MPN-U), STAT3 (only in T-NHL and NK cell neoplasm, 52% and 23%), NOTCH1 and PHF6 (T-ALL, 38% and 30%) and MYC and ID3 (almost exclusively in BL, 30% each). Genes predominantly mutated in myeloid neoplasms comprised e.g. SF3B1 (with the exception of CLL), JAK2, NPM1, RUNX1, IDH2, CEBPA, STAG2, NF1 and GATA2. By contrast, mutations in KMT2D, MYD88, ARID1A, ATM, CXCR4, BIRC3 and CD79B were detected almost exclusively in lymphoid malignancies. A broad distribution across entities was observed