Progress in the Genetics of Myelodysplastic Syndromes with a Latin American Perspective
Abstract
:1. Introduction
2. Overview of Molecular Characterization Studies
3. Key Molecular Mechanisms Driving MDS Pathogenesis
3.1. RNA Splicing
3.2. Chromatin Modification
3.3. DNA Methylation
3.4. Transcriptional Regulation
3.5. DNA Damage Response
3.6. Signal Transduction
3.7. Other Mechanisms
4. Molecular Genetics Data Integrated for Prognostic Risk Stratification in MDS, Including Artificial Intelligence
5. Molecular Data Incorporated in Current Diagnostic Classifications and New Proposals
6. Molecular Data to Tailor Treatment Strategies
7. Germline Predisposition: Implications and Challenges in Latin America
7.1. Main Syndromes
7.2. When to Suspect and How to Diagnose a Germline Predisposition
8. Molecular Tools in Latin America
9. Conclusions and Perspectives
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
MDS | Myelodysplastic syndromes |
AML | Acute myeloid leukemia |
AL | Acute leukemia |
WHO | World Health Organization |
ICC | International Consensus Classification |
SEER | Surveillance, Epidemiology, and End Results |
CMML | Chronic myelomonocytic leukemia |
NGS | Next-generation sequencing |
CNV | Copy number variations |
IPSS-R | International Prognostic Scoring System Revised |
IPSS-M | International Prognostic Scoring System Molecular |
OS | Overall Survival |
LFS | Leukemia Free Survival |
VAF | Variant allele frequency |
HMA | Hypomethylating agents |
CHIP | Clonal hematopoiesis of indeterminate potential |
PFS | Progression free survival |
AIPSS | Artificial Intelligence Prognostic Scoring System |
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Author/Year | N/Diagnosis | Region | Methods | Median Follow-Up | Main Findings |
---|---|---|---|---|---|
Kewan et al./2023 [115] | 3588/MDS and sAML | USA and Europe | NGS (40 genes) + ML | NI | MDS classification, prognostication, and prediction of treatment response, based solely on genetic factors (based on karyotype and mutation status). Fourteen molecularly distinct clusters. Correlation with OS (independent of IPSS-M) and response to treatment. |
Huber et al./2023 [114] | 735/De novo MDS | Europe (Germany) | WGS | 9.3 years | MDS classification and prognostication based solely on genetic. Nine genetically defined, mutually exclusive hierarchical subgroups (based on karyotype and mutation status). Correlation with OS and IPSS-M risk groups. |
Mosquera et al./2023 [113] | 7202/MDS and sAML | Spain | ML | 4.9 years | Enhanced MDS prognostication based on non-molecular variables (traditional clinical and laboratory). The model, AIPSS-MDS, performed better than IPSS-R and similar to IPSS-M. Correlation with OS and LFS. |
Bernard et al./2024 [116] | 3233/MDS or related disorders | USA, Europe, and Japan | NGS (152-gene panel) | NI | Classification and prognostication based on gene mutations, copy-number alterations, and copy neutral loss of heterozygocity. Sixteen molecular groups and two residual groups with negative findings, with different OS. Prognosis of t-MDS and myelodysplastic/myeloproliferative neoplasms depended on genetic subtypes. |
Lincango et al./2024 [41] | 182/MDS or related disorders | Latin America (AR and UY) | NGS (various gene panels) | 1.9 years | AIPSS-MDS validation for prognosis, showing similar prognostic discrimination to IPSS-M. AIPSS-MDS useful in resource-limited centers without molecular testing. |
Group | Entity | % | Reported Features |
---|---|---|---|
Validated five established subgroups | DDX41 | 3.3 | 56% of patients with mutated DDX41 had both a putative germline DDX41 variant (defined here as >30% VAF) and a somatic DDX41 mutation, 37% had only a putative germline DDX41 variant, and 7% had only somatic DDX41 mutations. |
AML-like | 2.0 | NPM1 mutations or at least 2 events from WT1, FLT3, MLLPTD, or MYC mutations. | |
TP53 complex | 10.0 | Multi-hit TP53 mutations were present in 74% of cases, of which 91% had a complex karyotype. | |
del(5q) | 6.9 | Presence of del(5q) as the sole cytogenetic abnormality or with 1 additional abnormality excluding −7/7q. Monoallelic TP53 mutations were significantly enriched in this group. | |
SF3B1 | 14.0 | Indolent clinical course. | |
Confirmed three previously reported subgroups | Bi-allelic TET2 | 13.0 | Early biallelic TET2 mutations with splicing factor mutations in 80% of patients, most commonly affecting SRSF2, SF3B1, or ZRSR2. Modulation of phenotype by ASXL1 and RAS mutations driving monocytosis and JAK2 driving thrombocytosis. |
der(1;7) | 0.5 | ETNK1 mutations were enriched in this group. | |
CCUS-like | 6.9 | 46% had a single mutated gene (TET2 or DNMT3A), 8% had loss of Y without gene mutations, and 6% had only ≥2 DTA mutations. | |
Eight novel subgroups | “−7/SETBP1” | 4.9 | SETBP1 mutations and/or −7 in the absence of complex karyotype. GATA2 variants were prevalent. |
EZH2-ASXL1 | 4.0 | ASXL1 and EZH2 mutation co-occurrence. High molecular complexity (75% of patients with ≥5 mutated genes). | |
IDH-STAG2 | 8.9 | Mutations at the IDH2 R140 hot spot, IDH1, and/or STAG2 co-occurring with either SRSF2 or ASXL1 mutations | |
BCOR/L1 | 3.5 | 83% of patients had mutations in BCOR, 33% in BCORL1, and 17% in both genes. | |
U2AF1 | 4.3 | 58% had a Q157 mutation, 41% had a S34 mutation, and 1% had both. | |
SRSF2 | 2.2 | Aggressive disease. | |
ZRSR2 | 1.3 | Indolent clinical course. | |
Two subgroups without defining genetic events | Not otherwise specified | 7.9 | Presence of other cytogenetic abnormalities and/or mutations in 51 other recurrently mutated genes. |
No event | 6.5 | Absence of any recurrent drivers evaluated. |
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Basquiera, A.L.; Andreoli, V.; Grille, S.; Belli, C.B. Progress in the Genetics of Myelodysplastic Syndromes with a Latin American Perspective. Genes 2025, 16, 687. https://doi.org/10.3390/genes16060687
Basquiera AL, Andreoli V, Grille S, Belli CB. Progress in the Genetics of Myelodysplastic Syndromes with a Latin American Perspective. Genes. 2025; 16(6):687. https://doi.org/10.3390/genes16060687
Chicago/Turabian StyleBasquiera, Ana Lisa, Verónica Andreoli, Sofía Grille, and Carolina Bárbara Belli. 2025. "Progress in the Genetics of Myelodysplastic Syndromes with a Latin American Perspective" Genes 16, no. 6: 687. https://doi.org/10.3390/genes16060687
APA StyleBasquiera, A. L., Andreoli, V., Grille, S., & Belli, C. B. (2025). Progress in the Genetics of Myelodysplastic Syndromes with a Latin American Perspective. Genes, 16(6), 687. https://doi.org/10.3390/genes16060687