Publication Date:
2014-12-06
Description:
Purpose: Chronic myelomonocytic leukemia (CMML) is a clinically heterogeneous myelodysplastic/myeloproliferative neoplasm with short overall survival. Emerging data based on sequencing of candidate genes with a known role in myeloid leukemia have identified recurrent CMML mutations, some of which have been associated with poor prognosis. A comprehensive evaluation of the mutational landscape of CMML and its prognostic significance is lacking. Patients and Methods. We comprehensively characterized the mutational landscape of CMML by a 2-step design. We initially performed whole exome sequencing (WES) of paired leukemia and germline DNA from 21 patients with a confirmed CMML diagnosis (discovery cohort) to identify genes with somatic mutations. From this discovery cohort, 215 genes showing potential mutations as well as 61 genes selected from the literature were examined by targeted resequencing in a second cohort of 69 clinically annotated CMML patients, using two independent platforms for orthogonal confirmation Blood or marrow samples from 22 young and 17 old controls were included as controls. Results. We identified 22 genes with mutations in 〉3% of CMML patients, and 67/69 patients (97%) had one or more mutations in at least one of these genes. SRSF2, ASXL1 and TET2 were the most frequently mutated genes. Several novel CMML genes were identified, including FAT4 with a mutation prevalence of 10% and BCR, CBFA2T3, and TRPM1 with a prevalence of 3 – 9% (see Table). Total deleterious mutations per patient ranged from 0 – 11, with significant exclusion or association of various combinations of mutations in SETBP1, ASXL1, KRAS, TET2, and EZH2 observed. In univariate analysis hemoglobin 〈 9g/dL, white blood cell count 〉 15x109/L, no treatment with hypomethylating agents, mutations in ASXL1, EZH2, or NRAS and mutations in growth factor signaling genes were associated with shorter overall survival. In multivariate analysis, mutations in NRAS (P
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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