Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients

Autor: A Gural, Dina Ben-Yehuda, N Goldschmidt, S Krichevsky, D Rund, S Ben-Neriah, S Shafran-Tikva, M Kedmi, S Bar-Cohen, E Malik
Rok vydání: 2005
Předmět:
Male
Oncology
Cancer Research
medicine.medical_specialty
Pathology
Time Factors
MLH1
Polymerase Chain Reaction
Ribosomal Protein S6 Kinases
90-kDa
Cytochrome P-450 Enzyme System
Risk Factors
hemic and lymphatic diseases
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Genotype
medicine
Genetic predisposition
Cytochrome P-450 CYP3A
Humans
Genetic Predisposition to Disease
neoplasms
Adaptor Proteins
Signal Transducing
Retrospective Studies
Leukemia
Hematology
business.industry
Cytogenetics
Nuclear Proteins
Microsatellite instability
Neoplasms
Second Primary
Middle Aged
Prognosis
medicine.disease
Immunohistochemistry
Survival Analysis
Neoplasm Proteins
MSH2
Karyotyping
Myelodysplastic Syndromes
Female
Genes
MDR
Carrier Proteins
MutL Protein Homolog 1
business
Microsatellite Repeats
Zdroj: Leukemia. 19:1919-1928
ISSN: 1476-5551
0887-6924
Popis: Therapy-related leukemia or myelodysplasia (t-leuk/MDS) is a serious problem that is increasing in frequency. We studied the clinical characteristics of 96 patients (pts) with a mean age of 48 years, and analyzed the molecular parameters that could predispose to t-leuk/MDS. Hematological malignancies were the most common primary (53%), followed by breast and ovarian cancer (30% combined). The mean latency until the development of t-AML was 45.5 months. Median survival was 10 months. Cytogenetics was abnormal in 89% of pts. FLT3 internal tandem duplications were found in six of 41 (14.6%) pts, of whom four had an abnormal karyotype. Analysis of drug metabolism and disposition genes showed a protective effect of the CYP3A4 1*B genotype against the development of t-leuk/MDS, whereas the CC genotype of MDR1 C3435T and the NAD(P)H:quinone oxidoreductase1 codon 187 polymorphism were both noncontributory. Microsatellite instability (MSI) analysis using fluoresceinated PCR with ABI sequence analyzer demonstrated that 41% of pts had high levels of MSI in four or more of 10 microsatellite loci. Immunohistochemistry demonstrated reduced expression of MSH2 and MLH1 in 6/10 pts with MSI as compared to 0/5 of pts without MSI. In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS.
Databáze: OpenAIRE
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