Co-mutation pattern, clonal hierarchy, and clone size concur to determine disease phenotype of SRSF2P95-mutated neoplasms
Autor: | Maria Creignou, Anna Gallì, Paola Guglielmelli, Mario Cazzola, Johanna Ungerstedt, Seishi Ogawa, Silvia Catricalà, Ettore Rizzo, Marios Dimitriou, Eva Hellström-Lindberg, Elisa Bono, Alessandro M. Vannucchi, Martina Sarchi, Elisa Rumi, Luca Malcovati, Vittorio Rosti, Yasuhito Nannya, Marco Roncador, Daniela Pietra, Chiara Elena, Elisabetta Molteni, Gabriele Todisco |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Genetics Cancer Research education.field_of_study Myeloid Genetic heterogeneity Myelodysplastic syndromes Population Myeloid leukemia Hematology Biology medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Oncology Monocytosis hemic and lymphatic diseases 030220 oncology & carcinogenesis medicine education Myelofibrosis Dominance (genetics) |
Zdroj: | Leukemia. 35:2371-2381 |
ISSN: | 1476-5551 0887-6924 |
Popis: | Somatic mutations in splicing factor genes frequently occur in myeloid neoplasms. While SF3B1 mutations are associated with myelodysplastic syndromes (MDS) with ring sideroblasts, SRSF2P95 mutations are found in different disease categories, including MDS, myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML). To identify molecular determinants of this phenotypic heterogeneity, we explored molecular and clinical features of a prospective cohort of 279 SRSF2P95-mutated cases selected from a population of 2663 patients with myeloid neoplasms. Median number of somatic mutations per subject was 3. Multivariate regression analysis showed associations between co-mutated genes and clinical phenotype, including JAK2 or MPL with myelofibrosis (OR = 26.9); TET2 with monocytosis (OR = 5.2); RAS-pathway genes with leukocytosis (OR = 5.1); and STAG2, RUNX1, or IDH1/2 with blast phenotype (MDS or AML) (OR = 3.4, 1.9, and 2.1, respectively). Within patients with SRSF2-JAK2 co-mutation, JAK2 dominance was invariably associated with clinical feature of MPN, whereas SRSF2 mutation was dominant in MDS/MPN. Within patients with SRSF2-TET2 co-mutation, clinical expressivity of monocytosis was positively associated with co-mutated clone size. This study provides evidence that co-mutation pattern, clone size, and hierarchy concur to determine clinical phenotype, tracing relevant genotype-phenotype associations across disease entities and giving insight on unaccountable clinical heterogeneity within current WHO classification categories. |
Databáze: | OpenAIRE |
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