Clinical and biological implications of driver mutations in myelodysplastic syndromes

Abstract

Key Points• MDS is characterized by mutations in .40 genes, a complex structure of gene-gene interactions and extensive subclonal diversification.• The total number of oncogenic mutations and early detection of subclonal mutations are significant prognostic variables in MDS.Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application. (Blood. 2013;122(22):3616-3627) Continuing Medical

Targeted deep sequencing of CD34+ cells from peripheral blood can reproduce bone marrow molecular profile in myelodysplastic syndromes

“…As previously reported we detected an increased number of genetic lesions in high‐risk WHO subtypes (Supporting Information Figure S3A) and found a correlation between the average number of genetic aberrations and the IPSS‐R prognostic risk score (Supporting Information Figure S3B) 1, 2. Interestingly, low risk patients displayed an increased number of somatic mutations compared to the number of lesions detected by CBA or SNP‐A.…”

“…To identify molecular markers of clinical relevance, we screened genes previously reported to be frequently mutated in MDS and other myeloid malignancies 1, 2. The somatic origin of the variants was validated by comparison of the concurrent samples (BMC, PB‐CD34, and PB‐MC) with a paired germline sample, peripheral CD3 + cells (PB‐CD3).…”

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

“…In a large MDS study (n 5 738), it was noted that the LFS steadily declined as the number of driver mutations increased (78% had at least one; while 43% had 2 or 3 and 10% had 4 to 8 mutations, respectively) [25]. This finding was not seen in patients with CMML [19].…”

“…Oncogenic driver mutations are seen in 80% of MDS patients (SF3B1 24%, TET2 22%, SRSF2 15% and ASXL1 15%) [25]. In a large MDS study (n 5 738), it was noted that the LFS steadily declined as the number of driver mutations increased (78% had at least one; while 43% had 2 or 3 and 10% had 4 to 8 mutations, respectively) [25].…”

Incidence of ATRX mutations in myelodysplastic syndromes, the value of microcytosis

“…In a large MDS patient series [6], the incidence of ATMDS was below 0.5%, but that paper contained no information about ATRX gene function, in particular the presence of microcytosis. On the other hand, a study reports data compilation which characterized specifically ATMDS [5].…”