Somatic mutations in splicing factor genes frequently occur in the myeloid neoplasms. While SF3B1 mutations are mainly associated with myelodysplastic syndromes (MDS) with ring sideroblasts, SRSF2-P95 mutations are found in different disease categories, including MDS, myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms MDS/MPN, and acute myeloid leukemia (AML). To identify the molecular determinants of this phenotypic heterogeneity, we explored the molecular and clinical features of a prospective cohort of 279 SRSF2-P95 - mutated cases selected from a population of 2663 patients with myeloid neoplasms. The median number of somatic mutations per each subject was three. A multivariate regression analysis showed the presence of 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); STAG2, RUNX1, or IDH1/2 with blast phenotype (MDS or AML) (OR=3.4, 1.9 and 2.1, respectively). Within patients with a SRSF2-JAK2 co-mutation, JAK2-dominance was invariably associated with clinical features of MPN, whereas the SRSF2 mutation was dominant in MDS/MPN. Moreover, within patients with a SRSF2-TET2 co-mutation, the clinical expressivity of monocytosis was positively associated with the co-mutated clone size. In conclusion, this study provides evidence that co-mutation pattern, clone size and hierarchy concur to determine the clinical phenotype of myeloid neoplasms-affected patients, tracing relevant genotype-phenotype associations across disease entities and giving insight on the unaccountable clinical heterogeneity within the current WHO classification categories.
Pattern co-mutazionali, gerarchia e dimensioni clonali nelle neoplasie mieloidi con mutazioni di SRSF2-P95 Le neoplasie mieloidi sono frequentemente interessate dall'occorrenza di mutazioni somatiche nei geni codificanti per i fattori di splicing. Mentre le alterazioni del gene SF3B1 sono prevalentemente associate alle sindromi mielodisplastiche (MDS) con sideroblasti ad anello, le mutazioni di SRSF2-P95 interessano diverse patologie, fra cui le MDS, le neoplasie mieloproliferative (MPN), le neoplasie mielodisplastiche/mieloproliferative (MDS/MPN) e la leucemia mieloide acuta (AML). Allo scopo di identificare i determinanti molecolari di tale eterogeneità fenotipica, abbiamo analizzato, in uno studio prospettico di coorte, le caratteristiche molecolari e cliniche di un campione di 279 pazienti con mutazioni di SRSF2-P95, selezionati fra una popolazione di 2663 individui affetti da neoplasie mieloidi. All’interno del campione, le mutazioni somatiche erano in media tre per ciascun soggetto. Un’analisi di regressione multivariata ha rivelato le seguenti associazioni fra i geni co-mutati con SRSF2 ed il fenotipo clinico: mutazioni di JAK2 o di MPL con mielofibrosi (OR=26.9); mutazioni di TET2 con monocitosi (OR=5.2); mutazioni dei geni del RAS pathway con leucocitosi (OR=5.1); e mutazioni di STAG2, RUNX1 or IDH1/2 con un fenotipo caratterizzato dalla presenza di blasti, nel contesto di MDS o di AML (OR=3.4, 1.9 e 2.1, rispettivamente). Fra i pazienti con co-mutazione di SRSF2 e JAK2, la dominanza clonale di JAK2 era invariabilmente associata ad un quadro clinico di MPN, mentre la mutazione di SRSF2 era dominante in MDS/MPN. Inoltre, all’interno dei pazienti con co-mutazione di SRSF2 e TET2, l’espressività clinica di monocitosi era positivamente associata alla dimensione del clone co-mutato. Questo studio dimostra dunque che il pattern co-mutazionale, la dimensione e la gerarchia clonali concorrono a determinare il fenotipo clinico dei pazienti affetti da neoplasie mieloidi, descrivendo associazioni genotipo-fenotipo rilevanti fra le diverse entità, ed illustrando l’incredibile eterogeneità clinica che caratterizza le varie categorie patologiche secondo l'attuale classificazione WHO.
Co-mutation patterns, clonal hierarchy and clone size in SRSF2-P95 - mutated myeloid neoplasms
CAMILOTTO, VIRGINIA
2019/2020
Abstract
Somatic mutations in splicing factor genes frequently occur in the myeloid neoplasms. While SF3B1 mutations are mainly associated with myelodysplastic syndromes (MDS) with ring sideroblasts, SRSF2-P95 mutations are found in different disease categories, including MDS, myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms MDS/MPN, and acute myeloid leukemia (AML). To identify the molecular determinants of this phenotypic heterogeneity, we explored the molecular and clinical features of a prospective cohort of 279 SRSF2-P95 - mutated cases selected from a population of 2663 patients with myeloid neoplasms. The median number of somatic mutations per each subject was three. A multivariate regression analysis showed the presence of 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); STAG2, RUNX1, or IDH1/2 with blast phenotype (MDS or AML) (OR=3.4, 1.9 and 2.1, respectively). Within patients with a SRSF2-JAK2 co-mutation, JAK2-dominance was invariably associated with clinical features of MPN, whereas the SRSF2 mutation was dominant in MDS/MPN. Moreover, within patients with a SRSF2-TET2 co-mutation, the clinical expressivity of monocytosis was positively associated with the co-mutated clone size. In conclusion, this study provides evidence that co-mutation pattern, clone size and hierarchy concur to determine the clinical phenotype of myeloid neoplasms-affected patients, tracing relevant genotype-phenotype associations across disease entities and giving insight on the unaccountable clinical heterogeneity within the current WHO classification categories.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/12054