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

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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.

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Acknowledgments

The authors would like to thank to Irene Rodríguez, Sara González, Teresa Prieto, María Ángeles Ramos, Filomena Corral, Almudena Martín, Ana Díaz, Ana Simón, María del Pozo, Isabel M Isidro, Vanesa Gutiérrez, Sandra Pujante, and María Angeles Hernández of the Cancer Research Center of Salamanca, Spain, for their technical assistance.

Funding

This work was supported by grants from the following: Contrato Rio Hortega, CM17/00171; Gerencia Regional de Salud (Castilla y León) para proyectos de investigación año 2018, 1850/A/18; Spanish Fondo de Investigaciones Sanitarias, PI15/01471, PI18/01500; Instituto de Salud Carlos III (ISCIII); European Regional Development Fund (ERDF) “Una manera de hacer Europa”; Consejería de Educación, Junta de Castilla y León (SA271P18); Proyectos de Investigación del SACYL, Spain, GRS1847/A/18, GRS1653/A17; SYNtherapy, Synthetic Lethality for Personalized Therapy-based Stratification In Acute Leukemia (ERAPERMED2018–275); ISCIII (AC18/00093), co-funded by ERDF/ESF, “Investing in your future”, by grants from Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD12/0036/0069) and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC CB16/12/00233). JMHS is supported by a research grant from Fundación Española de Hematología y Hemoterapia. MM is currently supported by an Ayuda predoctoral de la Junta de Castilla y León from the Fondo Social Europeo (JCYL- EDU/556/2019 PhD scholarship).

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Author notes

  1. Kamila Janusz, Marta Martín Izquierdo, María Abáigar and María Díez Campelo contributed equally to this work.

Authors and Affiliations

  1. Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-Universidad de Salamanca (IBMCC, USAL-CSIC); Genética Molecular en Oncohematología, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain

    Kamila Janusz, Marta Martín Izquierdo, Jesús María Hernández Sánchez, Eva Lumbreras, Cristina Robledo, Sandra Santos Mínguez, Cristina Miguel García, Ana María Simón Muñoz, Jesús María Hernández Rivas & María Abáigar

  2. Hematología, Hospital Universitario de Salamanca, Paseo de San Vicente, 182, 37007, Salamanca, Spain

    Félix López Cadenas, Juan Carlos Caballero, Jesús María Hernández Rivas & María Díez Campelo

  3. Hematología, Hospital Universitario de León, León, Spain

    Fernando Ramos & Javier Sánchez del Real

  4. Hematología, Hospital General Universitario de Valencia, Valencia, Spain

    Rosa Collado

  5. Hematología, Hospital Universitario Central de Asturias, Oviedo, Spain

    Teresa Bernal

  6. Hematología, Instituto Hospital del Mar de Investigaciones Médicas (IMIM), Barcelona, Spain

    Carme Pedro

  7. Hematología, Hospital Universitario Marqués de Valdecilla, Santander, Spain

    Andrés Insunza

  8. Hematología, Hospital Universitario de la Paz, Madrid, Spain

    Raquel de Paz

  9. Hematología, Hospital Universitari Germans Trias I Pujol, Instituto Catalán de Oncología (ICO), Badalona, Spain

    Blanca Xicoy

  10. Hospital Universitario de Canarias, Universidad La Laguna, San Cristóbal de La Laguna, Spain

    Eduardo Salido

  11. Hematología, Hospital Universitario Reina Sofía, Córdoba, Spain

    Joaquín Sánchez García

  12. Departamento de Estadística, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain

    Mercedes Sánchez Barba

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  1. Kamila Janusz
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  2. Marta Martín Izquierdo
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  3. Félix López Cadenas
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Correspondence to María Díez Campelo.

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Janusz, K., Izquierdo, M.M., Cadenas, F.L. et al. Clinical, biological, and prognostic implications of SF3B1 co-occurrence mutations in very low/low- and intermediate-risk MDS patients. Ann Hematol 100, 1995–2004 (2021). https://doi.org/10.1007/s00277-020-04360-4

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