Mutation profiling of 16 candidate genes in de novo acute myeloid leukemia patients

This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in de novo acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of de novo AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing. We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. FLT3-ITD was the most common mutated gene (16.2%, 42/259), followed by CEBPA (15.1%, 39/259), NRAS (14.7%, 38/259), and NPM1 (13.5%, 35/259). Concurrence was observed in 97.1% of the NPM1 mutated cases and in 29.6% of the double mutated CEBPA cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the IDH2 gene: R140 mutations were associated with NPM1 and/or FLT3-ITD mutations, whereas R172 mutations co-occurred with DNMT3A mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with NPM1 mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.

Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies

Whether Fanconi anemia(FA)heterozygotes are predisposed to bone marrow failure and hematologic neoplasm is a crucial but unsettled issue in cancer prevention and family consulting.We retrospectively analyzed rare possibly significant variations(PSVs)in the five most obligated FA genes,BRCA2,FANCA,FANCC,FANCD2,and FANCG,in 788 patients with aplastic anemia(AA)and hematologic malignancy.Sixty-eight variants were identified in 66 patients(8.38%).FANCA was the most frequently mutated gene(n=29),followed by BRCA2(n=20).Compared with that of the ExAC East Asian dataset,the overall frequency of rare PSVs was higher in our cohort(P=0.016).BRCA2 PSVs showed higher frequency in acute lymphocytic leukemia(P=0.038),and FANCA PSVs were significantly enriched in AA and AML subgroups(P=0.020;P=0.008).FA-PSV-positive MDS/AML patients had a higher tumor mutation burden,higher rate of cytogenetic abnormalities,less epigenetic regulation,and fewer spliceosome gene mutations than those of FA-PSV-negative MDS/AML patients(P=0.024,P=0.029,P=0.024,and P=0.013).The overall PSV enrichment in our cohort suggests that heterozygous mutations of FA genes contribute to hematopoietic failure and leukemogenesis.