Clinical mutations associated with MDS and their importance for disease outcome | Aplastic Anemia and MDS International Foundation

Clinical mutations associated with MDS and their importance for disease outcome

PubMed Abstract: 
Original Publication Date: 
Friday, November 22, 2013

Myelodysplastic syndrome (MDS) is not one disease, but represents a group of diseases.  Each group has distinct clinical and pathological abnormalities.  Some groups are associated with a specific genetic abnormality, others with a mixture of genetic abnormalities.  It is important to understand the significance of the individual abnormalities, because it may help doctors to design a better patient-specific treatment plan or develop entirely new drugs based on what we know about a specific mutation in a specific gene.

This study analyzed samples from 738 patients: 603 with MDS and 135 with diseases that have an important MDS component, including chronic myelomonocytic leukemia (CMML), MDS/acute myeloid leukemia (AML), MDS-unclassifiable and the overlap syndrome MDS/myeloproliferative neoplasm (MPN).  The DNA was harvested from blood and bone marrow cells from these patients and interrogated for the presence of mutations (DNA abnormalities) in 111 genes.  This panel of 111 genes was chosen based on prior knowledge: e.g., some were known to be associated with cancers when mutated, including myeloid blood cancers; others were chosen because the authors’ own (unpublished) studies had identified them as potential cancer-promoting genes when mutated. 

Using a so-called targeted sequencing technology, i.e., a method to decipher the genetic code of a limited set of specified genes, the integrity of these 111 genes was interrogated across 738 patients.  They found 2260 significant variations from the reference DNAs (based on 78 samples obtained from healthy individuals).  These variations were then classified as 1) oncogenic (i.e., tumor-causing) (based on previously published studies showing that these mutations are present at a significantly higher percentage than can be expected by chance, in myeloid diseases  2) potentially tumorigenic and 3) unknown.  The variations also included loss of duplications of chromosomal sections.  74% of MDS patients showed one or more oncogenic mutations or one of the larger chromosomal abnormalities.  Of note: classical chromosomal analysis (“cytogenetics”) identified abnormalities in 33% of MDS patients.  The two methods combined identified abnormalities in 78% of MDS patients, indicating that either method identifies some unique genetic abnormalities that the other cannot. 43% of MDS patients showed two or three of these variations, whereas ten had four to eight. 

Similar to what had been published before, the authors found a correlation between leukemia-free survival and mutated genes: mutations in one of 8 genes (TP53, U2AF1, RUNX1, SRSF2, IDH2, CUX1, ASXL1, BCOR) worsened leukemia-free survival, while mutated SF3B1 increased it.  Importantly, this study also found that it did not matter whether the mutated gene was found in all cells or only in a subset (clone); this stresses the importance of early detection of these gene mutations as an indicator of a potential aggressive disease, so that a more aggressive treatment plan can be initiated as early as possible, which may disease outcome.  Lastly, the total number of oncogenic mutations found in a patient turned out to be an important indicator of leukemia-free survival as well:  this was 49 months for patients with one oncogenic mutation, 42 for patients with two oncogenic mutations, and 27, 18 and four months for patients with three, four to five and more than 6 oncogenic mutations, respectively. 

Thus, it seems that sequencing of particular genes can be of great help in determining the aggressiveness of a patient’s disease, independently or in addition to the currently used parameters to classify MDS.  The far majority (80%) of MDS patients can be characterized by the methodology described in this study. Unfortunately, there is still a proportion of MDS patients (20%) for which no genetic markers can be identified.  For these patients, additional studies are still needed. 

Reviewer Bio: