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Frequência de mutações no gene SF3B1 em síndromes mielodisplásicos e leucemia linfocítica crónica
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Abstract(s)
Introdução: Recentemente foram identificadas mutações somáticas no gene que codifica a subunidade 1 do fator de splicing 3B – SF3B1 em neoplasias hematológicas, nomeadamente em síndromes mielodisplásicos (SMD), SMD/ neoplasias mieloproliferativas (SMD/NMP) e leucemia linfocítica crónica (LLC). Objetivo: Definir a prevalência de mutações no gene SF3B1 (exões 14 e 15) num grupo de doentes com SMD e SMD/NMP, e com LLC.
Material e métodos: Foram estudadas 74 amostras de doentes com SMD e SMD/NMP:1 citopenia refratária (CR),8 anemia refratária (AR),19 AR com sideroblastos em anel (SA) (ARSA), 13 citopenia refratária com displasia multilinha (CRDM), 2 CRDM com SA (CRDM-SA), 7 AR com excesso de blastos (AREB), 4 SMD com del(5q),10 SMD não classificado (SMD-U), 7 ARSA com trombocitose (ARSA-T) e 3 Leucemia mielomonocítica crónica (LMMC); e 80 com LLC, classificados de acordo com critérios da OMS 2008.O screening de mutações no exão 15 do gene SF3B1 foi efetuado por High Resolution Melting (HRM).O estudo dos exões 14 e 15 foi efetuado por PCR e sequenciação direta.
Resultados: Foram detetadas mutações missense em heterozigotia em 39.2% (29/74) dos doentes; foram identificadas 8 mutações diferentes, já previamente descritas: K700E (18), K666N/Q/E (6), R625C (2), H662D (1), N626D (1) e Y623C (1). Os doentes com mutação SF3B1 apresentavam: contagem de plaquetas mais elevada (p=0,006), maior percentagem de sideroblastos em anel (p<0,001), e percentagem de blastos na MO mais baixa (p<0,001) relativamente aos doentes sem mutação. A prevalência de mutações SF3B1 nos doentes com SA foi de 100% nas ARSA (19) e CRDM-SA (2) e de 85,7% nas ARSA-T (6/7). Dos 7 doentes com ARSA-T, 5 (71,4%) tinham, concomitantemente, as mutações JAK2V617F e SF3B1. A presença da mutação SF3B1 apresentou um valor preditivo positivo (VPP) de 100% (CI 95%, 87%-100%) para os SA (≥15%). Oito doentes (11,6%) evoluíram para LMA (apenas 1 ARSA com mutação SF3B1) e 19 (27%) morreram (6 com mutação SB3B1). A análise univariada não revelou de relação entre a existência de mutação SF3B1 e tempo de sobrevida (OS: p=0,73).
Discussão: Observou-se que todos os doentes com mutação SF3B1 têm percentagem de SA na MO ≥15% (p<0.0001), com um VPP de 100% (CI 95%, 87%-100%). Neste estudo, a presença de mutação SF3B1 não confere valor prognóstico favorável, ao contrário do sugerido por alguns autores.
Conclusão: Serão necessários mais estudos para elucidar o papel das mutações no gene SF3B1 na patofisiologia dos SMD com SA e a sua utilidade no diagnóstico e eventual estratégia terapêutica.
Introduction: Recently in hematological malignancies different groups identified somatic mutations in the gene encoding subunit 1 of the splicing factor 3B –SF3B1, particularly in myelodysplastic syndromes (MDS), MDS/ myeloproliferative neoplasias (SMD/MPN) and chronic lymphocytic leukemia (CLL). Objective: Define the prevalence of SF3B1 mutations (14 and 15 exons) in a group of patients with MDS and MDS/MPN and in a group of CLL patients. Material and methods: We studied 74 samples from patients with MDS and MDS/MPN: 1 refractory cytopenia (RC), 8 refractory anemia (RA), 19 RA with ring sideroblasts (RS) (RARS), 13 refractory cytopenia with multiline dysplasia (RCMD), 2 RCMD with RS (RCMD-RS), 7 RA with excess blasts (RAEB), 4 MDS del5q, 10 MDS unclassifiable (MDS-U), 7 RARS with thrombocytosis (RARS-T), and 3 chronic myelomonocytic leukemia (CMML); and 80 CLL patients, classified according to the WHO 2008 criteria. Mutations in SF3B1 exon 15 were screened by High Resolution Melting (HRM). Mutations in SF3B1 exons 14 and 15 were identified by PCR and direct sequencing. Results: Missense mutations were detected in heterozygosity in 39.2% (29/74) of patients; 8 different mutations, previously described, were identified: K700E (18), K666N/Q/E (6), R625C (2), H662D (1), N626D (1) and Y623C (1). Patients with SF3B1 mutations present higher platelet counts (p=0,006), higher ring sideroblasts percent (p<0,001), and lower blasts percent in BM (bone marrow) (p<0,001) when compared to patients without mutation. The prevalence of SF3B1 mutations in patients with RS was 100% in ARSA (19) and CRDM-SA (2), and 85,7% in RARS-T (6/7). Of the 7 patients with RARS-T, 5 (71,4%) had concomitant JAK2V617F and SF3B1 mutations. The presence of the SF3B1 mutation have a positive predictive value (PPV) of 100% (95% CI, 87%-100%) for the RS (≥15%). 8 patients (11,6%) progressed to AML (only 1 mutation SF3B1 ARSA) and 19 (27%) died (6 with SB3B1 mutation). Univariate analysis did not reveal a relationship between the presence of SF3B1 mutation and overall survival (OS: p=0,73). Discussion: We found that all patients with SF3B1 mutations have ≥15% of RS in BM (p<0,0001), with a PPV of 100% (95% CI, 87%-100%). In this study, the presence of SF3B1 mutation does not confer favorable prognostic value, unlike previously suggested by some authors. Conclusion: Further studies will be needed to elucidate the role of SF3B1 mutations in the pathophysiology of SMD, particularly in those characterized by RS, and its usefulness in the diagnosis and eventual therapeutic strategy.
Introduction: Recently in hematological malignancies different groups identified somatic mutations in the gene encoding subunit 1 of the splicing factor 3B –SF3B1, particularly in myelodysplastic syndromes (MDS), MDS/ myeloproliferative neoplasias (SMD/MPN) and chronic lymphocytic leukemia (CLL). Objective: Define the prevalence of SF3B1 mutations (14 and 15 exons) in a group of patients with MDS and MDS/MPN and in a group of CLL patients. Material and methods: We studied 74 samples from patients with MDS and MDS/MPN: 1 refractory cytopenia (RC), 8 refractory anemia (RA), 19 RA with ring sideroblasts (RS) (RARS), 13 refractory cytopenia with multiline dysplasia (RCMD), 2 RCMD with RS (RCMD-RS), 7 RA with excess blasts (RAEB), 4 MDS del5q, 10 MDS unclassifiable (MDS-U), 7 RARS with thrombocytosis (RARS-T), and 3 chronic myelomonocytic leukemia (CMML); and 80 CLL patients, classified according to the WHO 2008 criteria. Mutations in SF3B1 exon 15 were screened by High Resolution Melting (HRM). Mutations in SF3B1 exons 14 and 15 were identified by PCR and direct sequencing. Results: Missense mutations were detected in heterozygosity in 39.2% (29/74) of patients; 8 different mutations, previously described, were identified: K700E (18), K666N/Q/E (6), R625C (2), H662D (1), N626D (1) and Y623C (1). Patients with SF3B1 mutations present higher platelet counts (p=0,006), higher ring sideroblasts percent (p<0,001), and lower blasts percent in BM (bone marrow) (p<0,001) when compared to patients without mutation. The prevalence of SF3B1 mutations in patients with RS was 100% in ARSA (19) and CRDM-SA (2), and 85,7% in RARS-T (6/7). Of the 7 patients with RARS-T, 5 (71,4%) had concomitant JAK2V617F and SF3B1 mutations. The presence of the SF3B1 mutation have a positive predictive value (PPV) of 100% (95% CI, 87%-100%) for the RS (≥15%). 8 patients (11,6%) progressed to AML (only 1 mutation SF3B1 ARSA) and 19 (27%) died (6 with SB3B1 mutation). Univariate analysis did not reveal a relationship between the presence of SF3B1 mutation and overall survival (OS: p=0,73). Discussion: We found that all patients with SF3B1 mutations have ≥15% of RS in BM (p<0,0001), with a PPV of 100% (95% CI, 87%-100%). In this study, the presence of SF3B1 mutation does not confer favorable prognostic value, unlike previously suggested by some authors. Conclusion: Further studies will be needed to elucidate the role of SF3B1 mutations in the pathophysiology of SMD, particularly in those characterized by RS, and its usefulness in the diagnosis and eventual therapeutic strategy.
Description
Keywords
SF3B1 Neoplasias mieloproliferativas Síndromes mielodisplásicas Leucemia linfocítica crónica Sideroblastos em anel Myelodysplastic syndromes Myeloproliferative neoplasms Leukemia, lymphocytic, chronic, Ring sideroblasts