Microsatellite instability and p53 mutations in therapy-related leukemia suggest mutator phenotype

Abstract

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.

Microsatellite instability occurs in defined subsets of patients with acute myeloblastic leukaemia

“…This finding is supported by the results of two other studies that demonstrated an association between MSI and abnormalities of chromosomes 5 and 7 (Ben-Yehuda et al, 1996;Horiike et al, 1999). This association could, in part, be explained by the high incidence of p53 mutations seen in these cases (Ben-Yehuda et al, 1996;Zhu et al, 1999) as it has been demonstrated that deficiencies in wild-type p53 may allow unrepaired double strand DNA breaks to contribute to the development of chromosomal instability (Honma et al, 2000). Our results differ from those of Rimsza et al (2000) who have analysed the largest series of cases of AML, also using a fluorescent PCR-based technique.…”

“…We found a high incidence of adverse-risk cytogenetics, including abnormalities of chromosomes 5 and 7, in the group of patients with MSI and, although these numbers were too small to allow for accurate statistical analysis, they suggest an association between cytogenetic risk group and MSI and, hence, aberrant DNA repair. This finding is supported by the results of two other studies that demonstrated an association between MSI and abnormalities of chromosomes 5 and 7 (Ben-Yehuda et al, 1996;Horiike et al, 1999). This association could, in part, be explained by the high incidence of p53 mutations seen in these cases (Ben-Yehuda et al, 1996;Zhu et al, 1999) as it has been demonstrated that deficiencies in wild-type p53 may allow unrepaired double strand DNA breaks to contribute to the development of chromosomal instability (Honma et al, 2000).…”

“…Recently, we demonstrated MSI in association with abnormal expression of the MMR protein hMSH2 in a subset of elderly patients with AML and in patients with t-AML (Zhu et al, 1999). These patients also had a high incidence of p53 mutation, which was also noted by Ben-Yehuda et al (1996) in cases of t-AML.…”

“…Several studies have searched for MSI as evidence of MMR deficiency in acute myeloblastic leukaemia (AML) and myelodysplasia (Indraccolo et al, 1995;Kaneko et al, 1995;Robledo et al, 1995;Ben-Yehuda et al, 1996;Sill et al, 1996;Tasaka et al, 1996Tasaka et al, , 1997Boyer et al, 1998;Zhu et al, 1999;Maeck et al, 2000;Rimsza et al, 2000). Taken together, the results suggest that the incidence of MSI in de novo AML and myelodysplastic syndrome (MDS) is relatively low with estimates ranging from 0% (Rimsza et al, 2000) to 10% of cases studied (Sill et al, 1996;Tasaka et al, 1997).…”

“…The greatest variation between studies occurs in the case of therapy-related AML (t-AML). Ben-Yehuda et al (1996) reported MSI occurring in 15/16 (94%) cases of therapy-related AML (t-AML)). Three other groups have subsequently looked for MSI in t-AML and t-MDS but failed to find such a strong association, the reported incidence of MSI being 0% (Rimsza et al, 2000), 7% (Boyer et al, 1998) and 20% in the study by Horiike et al (1999).…”