GENETIC CONSIDERATIONS IN THE EVALUATION OF MYELOID DISEASES
Genetics as a Supportive Tool for Accurate Diagnosis of Myeloproliferative Disorders, Myelodysplasia, and Neoplasms
Back in 1953 a pre-leukemic state was described in a series of 12 patients,4
yet a clear pathological definition, classification, and naming the syndrome as myelodysplastic were established only in 1982 by the French–American–British (FAB) group.5
During the 32 years that followed the FAB classification, myelodysplastic syndrome (MDS) was reclassified twice,6,7
based on morphology. Currently isolated deletion of 5q is the only genetic aberration that has implication for MDS diagnosis and classification.
The torrent of novel genetic information is not yet reflected in the way MDS is being diagnosed and classified. The limitations of morphologic classification lead to the recognition of ill-defined entities.7 There is an unmet need for laboratory-supportive tools for the diagnosis and classification of morphologically challenging entities.8,9 The potential of genetic data that can support current diagnostic tools is of special importance when morphologic diagnosis is difficult, inconclusive, or non-reproducible by different morphologists. Newly identified driver mutations are found to be associated with otherwise poorly defined diseases and are likely to be included in future MDS or myeloproliferative neoplasm (MPN) classification. Examples for suggested driver mutations are the SET-binding protein 1 (SETBP1) in atypical chronic myeloid leukemia (aCML),10,11 SRSF2 in chronic myelomonocytic leukemia (CMML),12–14 and CSF3R in chronic neutrophilic leukemia.15,16 Another common diagnostic difficulty that can now be overcome using genetic information is the differentiation between primary myelofibrosis and other causes of bone marrow fibrosis. Either calreticulin (CALR) mutation or JAK2 mutation is revealed in most cases of primary myelofibrosis.17 It is therefore reasonable to anticipate incorporation of these mutations into future diagnostic and classification criteria.18,19
In low-risk MDS, criteria for quantitative enumeration of ring sideroblasts are available,20 but the techniques require well-trained morphologists and are time-consuming. One may consider that since the SF3B1 mutation has a positive predictive value for the presence of ring sideroblasts of 97.7%,21 this mutation will soon be recognized as supportive to the diagnosis of refractory anemia with ring sideroblasts. Chronic myelomonocytic leukemia (CMML) is currently classified, based on the level of the white blood cell count, into myelodys-plastic and myeloproliferative subcategories. It was recently suggested that such sub-classification could be better defined by specific genetic profiles.22,23
Understanding of the genetic basis of myeloid malignancies will inevitably lead in the near future to the incorporation of some of the above-mentioned genetic tests into the working schemes for hematologic diagnosis. Potentially, the identification of pre-leukemic mutations in AML24 may be the first step towards accomplishing a more challenging task, that of determining the boundaries between high-risk MDS or MPN and AML. In the future, genetics may enable molecular identification of patients in whom leukemic transformation would ensue prior to the appearance of traditional clinical and laboratory signs and symptoms.
Prognostication: Cytogenetics and Beyond
For many years, cytogenetics has been the only genetic information that influenced clinical decisions in MDS. The international prognostic scores both in their primary and revised versions (IPSS and R-IPSS)25,26
consider only patients who received supportive therapy and describe the natural history of the disease providing valuable predictions of prognosis. Recent large-scale, comprehensive genetic studies have provided description of the mutation landscape of MDS,27–29
identification of new mechanisms involved in disease pathogenesis,30–32
and confirmed that MDS is a stem cell disorder.18
Results of such exciting scientific progress are still waiting to be incorporated into daily clinical practice.
Unlike MDS, where cytogenetics allows segregation of patients into categories with a well-defined predicted outcome,33 the prognostic value of cytogenetics is much less prominent in CMML34–36 and primary myelofibrosis (PMF).37,38 In the absence of a strong cytogenetic influence, the prognostic value of specific mutations is recognized in these diseases. It is not clear whether these mutations have no effect in MDS or their prognostic value in this disease is masked by a strong cytogenetic influence. The ASXL1 mutation is most dominant in CMML39,40 and PMF,41,42 while mutations in other genes may also affect patient prognosis. The interplay between cytogenetic profile and prognostic power of specific mutations is highlighted by the finding that most MDS patients presenting with a complex karyotype also carry a mutation or a deletion in the well-known tumor suppresser gene TP53.43,44 Whether the aberrant karyotype or the TP53 mutation is responsible for the poor outcome of affected patients is still unknown.
The more we know about the genomic landscape of myeloid malignancies, the more complicated become the combinatorics of potential aberrations to be integrated for prediction of the outcome for a specific patient. Cytogenetics, mutations, micro-deletions, methylation abnormalities, and micro-RNA expression levels are all important players determining patient prognosis. It will therefore be challenging to create an ultimate prognostic model which will be much better than those available today. Physicians should focus on genetic aberrations that can influence therapeutic decisions in every given clinical situation. Examples and suggestions for such an approach are reviewed herein.
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