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. 2021 Aug;100(8):1995-2004.
doi: 10.1007/s00277-020-04360-4. Epub 2021 Jan 6.

Clinical, biological, and prognostic implications of SF3B1 co-occurrence mutations in very low/low- and intermediate-risk MDS patients

Kamila Janusz #  1 , Marta Martín Izquierdo #  1 , Félix López Cadenas  2 , Fernando Ramos  3 , Jesús María Hernández Sánchez  1 , Eva Lumbreras  1 , Cristina Robledo  1 , Javier Sánchez Del Real  3 , Juan Carlos Caballero  2 , Rosa Collado  4 , Teresa Bernal  5 , Carme Pedro  6 , Andrés Insunza  7 , Raquel de Paz  8 , Blanca Xicoy  9 , Eduardo Salido  10 , Joaquín Sánchez García  11 , Sandra Santos Mínguez  1 , Cristina Miguel García  1 , Ana María Simón Muñoz  1 , Mercedes Sánchez Barba  12 , Jesús María Hernández Rivas  1   2 , María Abáigar #  1 , María Díez Campelo #  13
Affiliations

Clinical, biological, and prognostic implications of SF3B1 co-occurrence mutations in very low/low- and intermediate-risk MDS patients

Kamila Janusz et al. Ann Hematol. 2021 Aug.

Abstract

SF3B1 is a highly mutated gene in myelodysplastic syndrome (MDS) patients, related to a specific subtype and parameters of good prognosis in MDS without excess blasts. More than 40% of MDS patients carry at least two myeloid-related gene mutations but little is known about the impact of concurrent mutations on the outcome of MDS patients. In applying next-generation sequencing (NGS) with a 117 myeloid gene custom panel, we analyzed the co-occurrence of SF3B1 with other mutations to reveal their clinical, biological, and prognostic implications in very low/low- and intermediate-risk MDS patients. Mutations in addition to those of SF3B1 were present in 80.4% of patients (median of 2 additional mutations/patient, range 0-5). The most frequently mutated genes were as follows: TET2 (39.2%), DNMT3A (25.5%), SRSF2 (10.8%), CDH23 (5.9%), and ASXL1, CUX1, and KMT2D (4.9% each). The presence of at least two mutations concomitant with that of SF3B1 had an adverse impact on survival compared with those with the SF3B1 mutation and fewer than two additional mutations (median of 54 vs. 87 months, respectively: p = 0.007). The co-occurrence of SF3B1 mutations with specific genes is also linked to a dismal prognosis: SRSF2 mutations were associated with shorter overall survival (OS) than SRSF2wt (median, 27 vs. 75 months, respectively; p = 0.001), concomitant IDH2 mutations (median OS, 11 [mut] vs. 75 [wt] months; p = 0.001), BCOR mutations (median OS, 11 [mut] vs. 71 [wt] months; p = 0.036), and NUP98 and STAG2 mutations (median OS, 27 and 11 vs. 71 months, respectively; p = 0.008 and p = 0.002). Mutations in CHIP genes (TET2, DNMT3A) did not significantly affect the clinical features or outcome. Our results suggest that a more comprehensive NGS study in low-risk MDS SF3B1mut patients is essential for a better prognostic evaluation.

Keywords: MDS; NGS; SF3B1; Splicing.

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