Clonal diversity of recurrently mutated genes in myelodysplastic syndromes

Abstract

Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ≤0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.

Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

“…17 By performing serial assessments before and after disease progression, as well as before and after induction chemotherapy, we resolved s-AML into a composite set of genetic lesions with distinct associations to ontogeny groups.…”

“…First, 8 genes were mutated with .95% specificity in s-AML compared with de novo AML, including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2, hereafter named "secondary-type" mutations ( Figure 1B). These 8 genes are also commonly mutated in MDS, 2,4,[6][7][8][9]17 suggesting that they may primarily drive the dysplastic differentiation and ineffective hematopoiesis that is characteristic of MDS, without efficiently promoting development of frank leukemia.…”

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

“…3,9 Mutational profiles confer important prognostic information that is independent of other traditional risk factors, including karyotype, blast percentage, and patient clinical characteristics in both acute myeloid leukemia and myelodysplastic syndrome. [10][11][12][13][14][15][16][17][18] The prognostic significance of mutations in therapy-related myeloid neoplasms has not been extensively characterized. Point mutations of the tumor suppressor gene TP53 represent the most frequent single genetic abnormality in therapyrelated myeloid neoplasms and are detected in 20-40% of therapy-related myeloid neoplasm patients compared with 5-20% in de novo acute myeloid leukemia and myelodysplastic syndrome.…”

Genetic characterization of acquired aplastic anemia by targeted sequencing

“…Considering the 25 genes that were recently analyzed by Walter et al 5 in MDS patients, and which were also included in our analysis, somatic mutations were found in 68% of MDS patients but only 2 (5.3%) AA patients, one of whom had likely progressed to MDS. Patients' characteristics of the Walter study and our study are listed in Online Supplementary Table S3.…”

“…4 Data by Walter and colleagues show that 74% of MDS patients harbor a mutation in at least one of 94 candidate genes, while mutations can still be found in 68% of MDS patients when a core set of 25 genes is analyzed. 5 We hypothesized that mutations that are found in MDS patients may also be present in patients with AA and, therefore, evaluated the mutation profile of 42 genes in AA patients.…”