Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 646-650
N-RAS gene mutation in patients with aplastic anemia and aplastic
anemia/ paroxysmal nocturnal hemoglobinuria during evolution to
clonal disease
Y. Mortazavi,
J. A. Tooze,
E. C. Gordon-Smith, and
T. R. Rutherford
From the Department of Haematology, St. George's Hospital Medical
School, London, United Kingdom.
Long-term survivors of aplastic anemia (AA) have a high incidence of
clonal disorders, in particular paroxysmal nocturnal hemoglobinuria
(PNH), myelodysplastic syndromes (MDS), and acute nonlymphocytic
leukemia. To investigate the potential involvement of N-RAS gene
mutations in the predisposition to leukemic evolution, a subset of
patients at potentially increased risk for clonal disease was selected
based on evidence of existing clonal evolution. Nine patients showed a
monoclonal pattern of X-chromosome inactivation, 18 demonstrated a PNH
clone, and in 3 MDS developed during the course of this study. No
mutations were detected during the aplastic phase of disease; 2 of 3 patients with MDS after AA also showed no mutations. However, in 1 patient in whom the disease transformed from AA/PNH to MDS, a mutation
of GGT 
GAT at N-RAS codon 13 became detectable, whereas the
PNH mutation disappeared. The authors conclude that N-RAS mutations are
not an early event preceding transformation of AA or AA/PNH to
leukemia. In a subset of patients, RAS mutations may occur at the time
of evolution to MDS, but preexisting RAS mutations do not explain the
propensity of AA to leukemogenesis. Although PNH is also associated
with leukemia, this may arise in the non-PNH cells, indicating that
PIG-A gene mutation is not per se oncogenic.
