RUN1, TP53, and NRAS were strongly associated with severe thrombocytopenia
and an increased proportion of bone marrow blasts.
TP53, EZH2, ETV6, RUNX1, and ASXL1 mutations were identified in 137 of
the 439 (31.2%) study patients.
TP53, EZH2, ETV6, RUNX1, and ASXL1 had prognostic significance independent
of other established risk factors, predicting poor overall survival.
According to the National Institutes of Health, the frequency and incidence
of myelodysplastic syndromes (MDS) is increasing in the US population
and is influenced by factors such as advancing age, the use of cytotoxic
and mutagenic therapies for cancer, and greater exposure to environmental
toxins. MDS is a heterogeneous group of disorders with some patients having
an insidious onset of the disease, while others experience dramatic presentations
including marrow failure or acute myeloid leukemia. The treatment is determined
by the prognostic risk as determined by prognostic scoring systems, such
as the International Prognostic Scoring System (IPSS) which incorporates
the clinical features, bone marrow and peripheral blood findings, and
karyotypic abnormalities. Approximately half of all patients have a normal
karyotype. Single gene mutations are not currently considered in prognostic
scoring systems but may be important in further defining MDS clinical
phenotypes, risk stratification, and appropriate therapies.
Gene mutations reported to influence overall survival include: TP53, NRAS,
RUNX1, TET2, and IDH1 and IDH2. Only TP53 gene mutations have been found
to be associated with poor prognostic markers, such as a complex karyotype.
Recent research reported by Bejar, et al. in the New England Journal of
Medicine examined the influence that independent somatic point mutations
may exert on the clinical phenotype and prognosis in a large group of
patients with MDS.
The researchers identified somatic mutations in 18 genes, including two
genes (ETV6 and GNAS) that were not previously reported to be mutated
in MDS patients. Several of the somatic mutations correlated with features
of a specific clinical phenotype which included certain cytopenias, blast
percentage, cytogenetic abnormalities, and overall survival. RUNX1, TP53,
and NRAS were strongly associated with severe thrombocytopenia and an
increased proportion of bone marrow blasts. Mutations in one or more of
these genes, TP53, EZH2, ETV6, RUNX1, and ASXL1, were identified in 137
of the 439 (31.2%) study patients and had prognostic significance independent
of other established risk factors, predicting poor overall survival.
This study demonstrates that somatic point mutations are common in MDS,
associated with specific clinical features, and predict poor overall survival,
independent of other established risk factors. The findings support a
role for identifying these specific mutations in explaining the heterogeneity
of the myelodysplastic syndromes and improving the risk stratification
of these patients for better therapeutic intervention.
References
Bejar, R., Stevenson, K., Abdel-Wahab, O., Galili, N., Nilsson, B., Garcia-Manero,
G., Kantarjian, H., Raza, A., Levine, R. L., Neuberg, D., and Ebert, B.
L. (2011). Clinical effect of point mutations in myelodysplastic syndromes.
The New England Journal of Medicine, 364(26):2496-2506.
Kaneko H, Misawa S, Horiike S, Nakai H, Kashima K. TP53 mutations emerge
at early phase of myelodysplastic syndrome and are associated with complex
chromosomal abnormalities. Blood 1995;85:2189-93.
Kita-Sasai Y, Horiike S, Misawa S, et al. International prognostic scoring
system and TP53 mutations are independent prognostic indicators for patients
with myelodysplastic syndrome. Br J Haematol 2001;115:309-12.