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Microsatellite instability and p53 mutations in therapy-related leukemia
suggest mutator phenotype
D Ben-Yehuda, S Krichevsky, O Caspi, D Rund, A Polliack, D Abeliovich, O Zelig, V Yahalom, O Paltiel, R Or, T Peretz, S Ben-Neriah, O Yehuda and EA Rachmilewitz
Department of Hematology, Hadassah University Hospital, Ein Karem,
Jerusalem, Israel.
During the last decade the frequency of therapy-related acute leukemia
(t-leuk) and myelodysplastic syndrome (t-MDS) has been increasingly
observed. Over the past 15 years, we treated 56 patients with t-leuk who
had received prior chemotherapy (39%), radiotherapy (11%), or both (45%).
The drugs received included alkylating agents and topoisomerase II
inhibitors. The primary tumors included hematological malignancies (49%)
and solid tumors such as breast or ovarian cancer. The median age at
diagnosis of the primary tumor was relatively young (43 years +/- 18).
Twelve patients had more than one primary tumor and 31 patients had a
family history of malignancy. Karyotypic abnormalities were found in 91% of
the patients. Prognosis was uniformly poor, with an overall median survival
of 10 months. Twelve of the 18 patients examined (67%) had a multidrug
resistance phenotype. P53 genes of the leukemic cells, as well as the
original tumors, were analyzed in 21 patients using polymerase chain
reaction (PCR) with single-stranded conformation polymorphism analysis
followed by sequencing. P53 mutations were identified in 38% of these
patients, a relatively high prevalence compared with other forms of MDS or
de novo acute myeloid leukemia. Mutations were nongermline and restricted
to the leukemic cells. We identified different p53 mutations in the various
primary tumors of individual patients. The presence of a mutator phenotype
was assessed by PCR analysis of microsatellites in eight loci (one
trinucleotide repeat sequence, four dinucleotide, and three mononuclear
repeat sequences). Microsatellite instability in two to seven loci were
found in 15 of 16 (94%) of the patients. This instability is compatible
with a mutator phenotype, which predisposes the patients to the development
of malignancies including t-leuk.
Volume 88,
Issue 11,
pp. 4296-4303,
12/01/1996
Copyright © 1996 by The American Society of Hematology
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