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4610 Early-Onset Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) without SF3B1 Mutations in Adults: Enrichment with Germline Variants in Genes Responsible for Congenital Sideroblastic Anemias

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Bone Marrow Failure Syndromes, Clinical Research, Diseases, Myeloid Malignancies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Sandra Novoa Jáuregui, MD1*, Tzu Chen2*, Sara Torres-Esquius, MSc3*, Salvador Carrillo-Tornel4*, Marta Santiago, MD5*, Teresa Bernal Del Castillo, MD, PhD6*, Francisca Maria Hernandez, MD7*, Alessandro Liquori, PhD5,8*, Ivan Martin Castillo9*, Mar Tormo, M.D.10, Barbara Tazon, PhD11*, Adoracion Blanco12*, Laura Palomo, PhD13*, Jose Cervera, MD, PhD14*, Francesc Bosch, MD, PhD15,16, David Valcarcel, MD, PhD1,17, Maria Diez-Campelo, MD, PhD18*, Julia Montoro, PhD19* and Andres Jerez, MD, PhD20*

1Department of Hematology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
2Hospital General Universitario Morales Meseguer, Murcia, Spain
3Vall d'Hebron Universitary Hospital, UCGH. Spain, Barcelona, Spain
4Hematology and Medical Oncology Department, University Hospital Morales Meseguer. CRH-IMIB, Murcia, Spain
5Hematology Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
6Servicio de Hematología, Hospital Universitario Central de Asturias Instituto de Investigación del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias, (IUOPA), Oviedo, Spain
7Department of Hematology, Hospital Virgen de las Nieves, Granada, Spain
8Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
9Clinic Universitary Hospital, INCLIVA, Valencia, ESP
10Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
11Department of Hematology, Department of Hematology, University Hospital Vall d’Hebron, University Autònoma of Barcelona (UAB). Experimental Hematology Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
12Department of Hematology, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain
13Experimental Hematology Unit,Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
14.., Valencia, Spain
15Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
16Department of Hematology, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain
17Vall d´Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebrón, Barcelona, Spain
18University Hospital of Salamanca, Salamanca, Spain
19Department of Hematology, Vall D'Hebron Hospital Universitari, Experimental Hema, Barcelona, ESP
20Hematology Department, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain


Acquired mutations in SF3B1 gene in myeloid neoplasms are classically associated with the presence of RS in Pearl Stain, ineffective erythropoiesis, and favorable prognosis. Nevertheless, in up to 20-25% of adults diagnosed with MDS with RS (WHO 2017), mutations in SF3B1 are not found, and molecular grounds for the presence of RS remain to be ascertained. The objective of our study was to investigate whether the presence of RS could be associated with germline variants in genes responsible for congenital sideroblastic anemia (CSA).


Patients diagnosed with de novo MDS between 16-60 years of age without previous organ dysfunction were recruited from 32 centers of GEMSD since 2016. Whole exomes were sequenced using HiSeq4000-NovaSeq6000-Illumina, paired tumor-germline samples. Mean depth was 100x, with 150 million reads per sample and quality Q30a>95%. Variants were analyzed using a bioinformatics pipeline: filtering intronic and synonymous variants and those with a population frequency >1%. The mutational state of SF3B1 was determined by Sanger Sequencing and Next Generation Sequencing (NGS). Germline variants were categorized according to American College of Molecular Genetics (ACMG) criteria. The list of genes related to CSA explored in this study is shown in Table 1.


Among 239 cases of adults diagnosed with early-onset MDS (mean age at diagnosis: 48 years, range 16-60), 58 (24%) patients presented with RS in bone marrow (mean RS: 28%). Of these 58 patients, acquired mutations in SF3B1 were not found in 32 (55%). Nine out of these 32 (25%) harbored a germline variant (two variants in one case) in genes responsible for CSA (Table 2): SLC25A38 (n=2), STEAP3 (n=2) FECH, ALAS2, GLRX5, SLC19A2, TRNT1 and IARS2. This frequency was statistically higher than in the SF3B1 and RS mutated group (n=23), with only one case with a germline variant in a CSA gene (p=0.013). It was also higher than in the non-RS cases (n=181), with only one case in this group (p<0.001). Using the Fisher's exact test, commonly used to perform enrichment, the odds ratios were also significant (p=0.033 and p<0.0001), respectively.

Among patients with RS, those carrying a CSA gene germline variant were younger (43 vs. 54 years, p=0.04), had a higher rate of neutropenia (1.8 vs. 2.6 x 10E9/L, p=0.02), and thrombocytopenia (151 vs. 259 x 10E9/L, p=0.03) than MDS-RS patients with SF3B1 mutated. Furthermore, MDS-RS with a germline variant in CSA genes had a lower mean percentage of RS than patients who acquired the mutation in SF3B1 (14% vs. 38%; p=0.003).


In our series, the frequency of MDS-RS without SF3B1 mutations is higher in early-onset adult MDS than the one reported in MDS in advanced age. Whole exome analysis allowed us to describe, for the first time, a significant enrichment of variants in genes causing CSA in young adults with RS and without acquired mutation in SF3B1.

Disclosures: Tormo: MSD: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Gilead: Honoraria; SOBI: Other: Participation on Data Safety Monitoring Board; Jannsen: Other: Support for attending meetings; Astellas: Honoraria; AbbVie: Honoraria; Jazz: Other: support for attending meetings. Bosch: BeiGene: Consultancy; Roche: Honoraria; Lilly: Consultancy; Mundipharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyospharm: Other; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Diez-Campelo: Gilead Sciences: Other: Travel expense reimbursement; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board fees. Jerez: Novartis: Consultancy; Astrazeneca: Research Funding; GILEAD: Research Funding; BMS: Consultancy.

*signifies non-member of ASH