Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes – Basic and Translational Studies: Poster I
Aim: To comprehensively characterize the molecular features of patients with myeloid neoplasms and i(17q).
Patients and Methods: Patients were selected by the presence of i(17q) and diagnosis of a myeloid neoplasm. Philadelphia positive CML were excluded. The cohort comprised 62 cases, 47 males and 15 females with a median age of 69 years (range: 30 – 87 years). Classification of all cases was performed by cytomorphology on peripheral blood and/or bone marrow smears according to the WHO. Chromosome banding and FISH analysis were performed in all cases. 19/27 cases with sole i(17q) were additionally analyzed by array CGH. All 62 samples were analyzed by next generation sequencing using a 29-gene panel targeting ASXL1, BCOR, BRAF, CALR, CBL, CSF3R, DNMT3A, ETV6, EZH2, FLT3-TKD, GATA1, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, and WT1. Variants of unknown significance were excluded from statistical analyses (n=14).
Results: Following WHO classification four of the 62 patients were diagnosed as MPN, 13 as MDS/MPN overlap, 24 as MDS, and 21 as AML. 27 cases showed i(17q) as sole abnormality, while 23 cases showed additional chromosome aberrations, and eight even a complex karyotype (>3 aberrations). Further four cases had two independent cell clones, with one harboring the sole i(17q) abnormality. Array CGH revealed that in 15/19 cases i(17q) was the only abnormality, while four patients showed additional aberrations (1-3 per patient): loss of 7p, 7q, 12p, gain of 13q, and CN-LOH 19p and 22q (n=2). The comprehensive mutational analyses revealed only 3/62 patients carrying no mutation, while a median of 3 mutations per patient was observed (range 0-6). The three most frequently mutated genes were ASXL1 (66%, 41/62), SRSF2 (65%, 40/62), and SETBP1 (48%, 30/62) with no association to any WHO entity, indicating the presence of this genetic profile also across entities beyond the expected overlap between different neoplasms. Following genes showed mutation frequencies >10%: TET2 (24%), ETV6 (16%), CBL (13%), TP53 (15%), RUNX1 (11%), and NRAS (10%), all genes known for adverse prognostic impact. Interestingly, mutations in the three most frequently mutated genes ASXL1, SRSF2, and SETBP1 often co-occurred (n=21) and ASXL1 and SRSF2 were rarely mutated alone (n=9; n=5), while SETBP1 was even never mutated solely, indicating acquirement of SETBP1 mutations during disease course. Therefore, SETBP1 mutations associated significantly with mutations in ASXL1 as well as SRSF2 (24/41 vs 6/21 in ASXL1 wild type (wt), p=0.033; 27/40 vs 3/22 in SRSF2 wt, p<0.001). Furthermore, mutations in ASXL1 associated significantly with i(17q) sole in comparison to cases with additional chromosomal aberrations (22/27 vs 19/35, p=0.032). Therefore, also cases harboring mutations in all three genes ASXL1, SRSF2, and SETBP1 associated with sole i(17q) (13/27 vs 8/35, p=0.058), indicating that these three mutations might be drivers of disease pathogenesis in this cytogenetic background. Reviewing the bone marrow morphology showed characteristic pseudo-Pelger-Huet anomaly in 36 of 59 (61%) analyzed smears. These changes were not associated with the cytogenetic profile, but showed a trend towards co-occurrence with ASXL1 mutations (27/39 vs 9/20 ASXL1 wt p=0.094).
Conclusion: 1) Myeloid neoplasms with i(17q) show a distinct molecular mutation pattern, accumulating prognostically adverse mutations. 2) Patients with sole i(17q) show co-occurring mutations in ASXL1, SRSF2, and SETBP1. 3) Frequency and co-existence of ASXL1, SRSF2, and SETBP1 mutations predispose these as driver mutations.
Disclosures: Meggendorfer: MLL Munich Leukemia Laboratory: Employment . Haferlach: MLL Munich Leukemia Laboratory: Employment , Equity Ownership . Kern: MLL Munich Leukemia Laboratory: Employment , Equity Ownership . Schnittger: MLL Munich Leukemia Laboratory: Employment , Equity Ownership . Haferlach: MLL Munich Leukemia Laboratory: Employment , Equity Ownership .
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