RESUMO
BACKGROUND: Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerate the progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet. METHODS: We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA. Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied. RESULTS: A total of 21 patients were confirmed the diagnosis of FA with the median age of BMF onset was 4-year-old. The number of patients manifested as congenital malformations and growth retardation were 20/21 and 14/21, respectively. BM dysplasia and cytogenetic abnormalities were found in 13/20 and 8/19 patients. All the patients with abnormal karyotypes also manifested as BM dysplasia or had evident blasts. Thirty-five different mutations were identified involving six genes and including twenty novel mutations. FANCA mutations contributed to 66.67% of cases. Eight patients harboring ALDH2-G/A genotype have a significantly younger age of BMF onset (p = 0.025). Within the 19 patients adhering to continuous follow-up, 15 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 29 months of follow-up, 8/19 patients died, seven of which were HSCT-related, and one patient who did not receive HSCT died from severe infection. CONCLUSIONS: The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.
Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Estudos de Associação Genética , Genótipo , Mutação , Fenótipo , Adolescente , Medula Óssea/patologia , Criança , Pré-Escolar , Quebra Cromossômica , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Cariótipo , MasculinoRESUMO
Chromosome translocation t(12;22)(p13;q12)/MN1-ETV6 and MN1 overexpression confer a subset of adverse prognostic AML but so far lack in-depth research. We focused on the clinical course and comprehensive genetic analysis of eight cases with t(12;22)(p13;q12) and one with t(12;17;22) (p13;q21;q13) to elucidate their molecular etiology and outcomes of allogeneic hemopoietic stem cell transplantation (allo-HSCT). The total incidence of t(12;22)(p13;q12) and related translocations was 0.32% in myeloid neoplasms. These patients were confirmed to have dismal prognosis when treated only with chemotherapy, and we firstly provided evidence that they can significantly benefit from timely allo-HSCT. Five cases were MN1-ETV6 positive, and a novel MN1-STAT3 fusion was identified in the patient with triadic translocation. Significant MN1 overexpression was observed in all three MN1-fusion-negative cases. Genetic analysis highlighted the evidence of an ectopic super-enhancer associated orchestrated mechanism of MN1 overexpression and ETV6 haploinsufficiency in t(12;22)(p13;q12) myeloid neoplasms, rather than the conventional thought of MN1-ETV6 fusion formation. We also disclosed the high concomitance of trisomy 8 and 531 Kbps focal 8q duplication in t(12;22)(p13;q12) cases. The new perspective about this entity of disease will enlighten further research to define the mechanism of tumorigenesis and discover effective treatments for MN1-driven malignancies.
Assuntos
Genômica/métodos , Síndromes Mielodisplásicas/genética , Transativadores/uso terapêutico , Fatores de Transcrição/genética , Translocação Genética/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transativadores/farmacologia , Proteínas Supressoras de Tumor/farmacologia , Proteínas Supressoras de Tumor/uso terapêutico , Adulto JovemRESUMO
Recurrent fusion genes (FGs) with clinical significances in leukemias are mainly mutually exclusive, and the coexistence of different FGs has been rarely reported. In this study, we retrospectively analyzed the incidence, genetic characteristics, and prognosis of leukemias with concurrent pathogenic FGs, which commonly reported in hematological malignancies in 8226 leukemia patients. A total of 25 patients with coexistence of double FGs were identified, accounting for 0.30% of all cases enrolled. More than half of the cases (14/25, 56%) were diagnosed as chronic myeloid leukemia in accelerated or blast phase, another six and five cases were acute myeloid leukemia and acute lymphocytic leukemia, respectively. Most cases (20/25, 80%) carried constitutively activated tyrosine kinases FGs (BCR-ABL1 or ETV6-PDGFRB) and transcription factors associated FGs simultaneously. Of the 11 patients with contemporaneous karyotype, 5 (45%) showed visible chromosomal abnormalities corresponding to both FGs. The concurrency of FGs was often associated with disease progressions. The prognosis was pessimistic for patients with concurrent FGs, even with the combination of targeted therapy and chemotherapy. Performing allogeneic hematopoietic stem cell transplantation as soon as possible after complete remission can ameliorate the dismal prognosis.
