<i>SH2B3</i> in myeloid neoplasms: Potential pathogenic role of variants of uncertain significance.

Abstract

e18584 Background: SH2B3 is an adaptor protein that downregulates JAK-STAT signaling by binding JAK2. Loss-of-function mutations in SH2B3 have been implicated in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and MDS/MPN. However, SH2B3 variants in myeloid neoplasms are classified as variants of uncertain significance (VUS), and their clinical relevance is poorly understood. This analysis aims to characterize the clinico-genomic features of patients with SH2B3 variants. Methods: We performed a single-center, retrospective study of patients with SH2B3 variants identified on myeloid targeted DNA-sequencing. Available clinical and genomic data were collected from electronic medical records. Results: Our cohort included 57 patients (62% female) with median age of 64 years. SH2B3 variants (all VUS) were largely SNVs (88%), with median VAF of 48.4% (4.2-79.1%). The most common variants were p.Glu395Lys (n=6), p.Asp485_Trp492del (n=5), and p.Ser213Arg (n=5), concentrated in PH and SH2 domains. Common pathogenic co-mutations (present in 41% of cases) included JAK2 (n=8), TET2 (n=7), and DNMT3A (n=5). Hematologic abnormalities were common: thrombocytosis (32%), anemia (30%), leukocytosis (28%), thrombocytopenia (25%), and basophilia (23%). Overall, 34 patients (60%) had a cytopenic (anemia, neutropenia, and/or thrombocytopenia) phenotype, and 20 (35%) had a cytoses (leukocytosis, polycythemia, and/or neutrophilia) phenotype. Bone marrow evaluation (n=44) showed hypocellularity (25%), megakaryocytic atypia (32%), and hyperplasia (30%); 16% harbored abnormal karyotypes. Notably, in patients without pathogenic co-mutations (n=33), characteristic hematologic abnormalities (thrombocytosis 30%, anemia 21%, and thrombocytopenia 21%) and bone marrow morphologic changes (megakaryocytic atypia 30%) were common. Only 6% of this subset had a myeloid malignancy diagnosis, suggesting underestimation of these neoplasms. Conclusions: SH2B3 variants are associated with frequent hematologic abnormalities and characteristic bone marrow morphologic changes, even in the absence of pathogenic co-mutations. Hence, detection of the SH2B3 variant, even if a VUS, should raise suspicion of MDS or MPN in appropriate context. External validation of our findings is being performed using NIH’s All of Us database, and updated results will be presented at the meeting. Clinico-genomic characteristics of patients with SH2B3 variants. All (N=57) SH2B3 Variants With Pathogenic Co-mutation (N=24) SH2B3 Variants Without Pathogenic Co-mutation (N=33) Age, median (range) 64 (20-87) 67 (33-87) 62 (20-82) Hematology Thrombocytosis, n (%) 18 (32%) 8 (33%) 10 (30%) Anemia, n (%) 17 (30%) 10 (42%) 7 (21%) Leukocytosis, n (%) 16 (28%) 9 (38%) 7 (21%) Thrombocytopenia, n (%) 14 (25%) 7 (29%) 7 (21%) Bone Marrow (n=44) Megakaryocytic atypia, n (%) 15 (34%) 8 (38%) 7 (30%) Dysplasia, n (%) 6 (14%) 4 (19%) 2 (9%)