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Clinical and prognostic impact of STAG2 mutations in myeloid neoplasms: the Mayo Clinic experience

Year: 2022

Type: article

Abstract: The stromal antigen 2 (STAG2) gene, located on chromosome Xq25, is a core component of the cohesin complex that functions on chromatin organization, transcriptional regulation, and postreplicative DNA repair.[1][2][3] STAG2 mutations (STAG2ms) are reported in 5% to 10% of myeloid neoplasms (MNs), mostly high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).4,5 Although few data are available on the frequency of STAG2ms alone, collectively, cohesin complex mutations are present in 8% of MDS, 12% of AML, and 10% of chronic myelomonocytic leukemia cases.It is considered 1 of 8 secondary-type mutations and are specific to secondary AML (sAML).6 STAG2ms correlate with MDS response to hypomethylating agents (HMAs) 3,5 but are linked to poor prognosis in MDS, 3,7,8 with conflicting data on AML outcome [8][9][10][11] and limited data on effects of hematopoietic stem cell transplantation (HSCT).Our single-institute retrospective study included 91 patients with STAG2m MN, whose charts were reviewed for clinical information after institutional review board approval.Patients were included at date of in-house STAG2-harboring next-generation sequencing (NGS) (performed at diagnosis or progression).Diagnosis was rendered according to World Health Organization classification 12,13 and MDS risk stratification according to the Revised International Prognostic Scoring System.14 BlueSky Software V7.40 was used for statistical analysis.Most patients were older (median age, 72 years) males (78%).MDS was the most common diagnosis (55%), followed by AML (29%), MDS/myeloproliferative neoplasm (MPN) overlap, and MPN.Of the MDS cases, 36 (72%) belonged to the excess blast subtype (MDS-EB) (including 17 MDS-EB1 and 19 MDS-EB2) and 23 (46%) were high or very high risk.None were of the ring sideroblast subtype (including the 8 patients carrying SF3B1m).Ten patients with AML (38%) had sAML, whereas 14 patients (15%) had therapy-related MN (t-MN) (including 10 and 8 who received prior chemotherapy and radiotherapy, respectively).By the European LeukemiaNet risk stratification, 18 of the AML cases were adverse risk, 7 intermediate, and 1 favorable risk.Twenty-eight patients (31%) had abnormal cytogenetics, with trisomy 8 being the most common (Table 1; supplemental Tables 234).None of the females had X-chromosome deletion.The median VAF of STAG2ms was 50% (range, 5% to 100%) and was significantly higher in males (P < .001),as expected of an X-linked gene.Corrected median VAF (accounting for X chromosome) was 29.5% and 27% in males and females (P = .5),respectively.There was no difference in VAF between diagnostic groups (P = .6),MDS subtypes (P = .7),high and non-high-risk MDS (P = .6),de novo AML (dnAML) (P = .2),and sAML or between t-MN and de novo MN (dnMN) (P = .1).There was no correlation between VAF and bone marrow (BM) or peripheral blasts.Most STAG2ms were in the N-terminus (64%) and 15 (16%) were in the STAG domain.Within the STAG domain, there were

Source: Blood Advances

DOI: 10.1182/bloodadvances.2022007937