SF3B1 Gene Mutations and Their Significance for Patients with Myelodysplastic Neoplasms (MDS)
Authors: Zemanova Zuzana , Aghova Tatiana , Lhotska Halka , Vondrackova Zuzana , Hodanova Lucie , Lizcova Libuse , Sotakova Slavka , Minarik Lubomir , Stopka Tomas , Jonasova Anna 
Published: December 2024

The mutations of splicing factor genes (e.g., SF3B1, SRSF2, U2AF1, ZRSR2) are found in approximately 60% of MDS patients and lead to the accumulation of R-loops and associated DNA damage, resulting in the activation of the ATR pathway in affected cells. The most commonly mutated gene is SF3B1. These are hotspot mutations, mostly missense substitutions, with K700E being the most common variant. SF3B1 mutations are strongly associated with MDS with ring sideroblasts, which has a relatively slower progression. However, the results are heterogeneous, so identifying additional features that may affect the prognosis of MDS patients with SF3B1 mutations could lead to a better understanding of the disease and improved treatment. The aims of the study were to assess the frequency of SF3B1 mutations, the prognostic value of different mutation variants, and the association of SF3B1 mutations with cytogenomic findings and co-mutations with other genes.
Bone marrow cells of 386 MDS patients were investigated using a combination of cytogenomic methods (G-banding, I-FISH, mFISH/mBAND, aCGH/SNP) and next-generation sequencing (NGS) with the Archer VariantPlex Myeloid panel (ITD), covering 75 genes associated with myeloid malignancies.
SF3B1 mutations were confirmed in 60/386 patients (15.5%). Among these, 29/60 cases (48.3%) had a normal karyotype, 8/60 (13.3%) had isolated del(5q), 9/60 (15.0%) had a complex karyotype, and 14/60 patients (23.3%) had other chromosomal aberrations. In accordance with previously published data, patients with mutated SF3B1 had better overall survival than patients with SF3B1 wildtype (p=0,018). K700E was the most common variant, detected in 34/60 cases (46.7%). The most common genes co-mutated with SF3B1 were TET2 (19 cases), DNMT3A (13 cases), RUNX1 (13 cases), ASXL1 (7 cases), TP53 (6 cases), and JAK2 (6 cases). For further analyses, patients with an SF3B1 mutation were divided into four groups based on cytogenomic and molecular findings: group SF3B1α[other co-mutation than SF3B1β; 30 cases], group SF3B1β[the co-mutation with any gene from BCOR, BCORL1, NRAS, RUNX1, SRSF2, STAG2; 18 cases], group SF3B1del5q [the presence with isolated del(5q) without other co-mutations; 3 cases] and group SF3B1complex [the association with complex karyotype; 9 cases]. Patients included in the SF3B1α had the most favorable IPSS-M prognostic score, while patients in the SF3B1complex category had the worst. Nine of the 60 SF3B1-mutated cases (15%) fell into the IPSS-M very high-risk category. Five of these patients had a complex karyotype (in three cases associated with a TP53 mutation and in one case associated with mutations of NRAS and RUNX1 genes). In two other patients, we detected the K666N variant of SF3B1 mutation, which is associated with increased progression of MDS and distinct RNA splicing. Of the nine patients in this group, six have died. Three are still alive and are undergoing azacitidine treatment at 6.5, 8.5, and 21 months after their diagnosis.
Identification of splicing factor gene mutations is an important diagnostic tool for the stratification of MDS patients. According to IPSS-M, SF3B1 mutations have a more favorable prognostic score compared to other splicing gene mutations (e.g., SRSF2 or U2AF1). However, the prognostic significance of individual variants may differ. Other biological factors such as the mutation variant, association with complex karyotypes, and mutations in other genes, may also affect the prognosis of patients with mutated SF3B1. Therefore, a comprehensive view that includes all cytogenomic, molecular, and clinical data is important for accurate diagnosis and personalized treatment of MDS patients.
Supported by MH CZ-DRO 0064165