Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients.
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.
Rund
D
D
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel. rund@cc.huji.ac.il
Krichevsky
S
S
Bar-Cohen
S
S
Goldschmidt
N
N
Kedmi
M
M
Malik
E
E
Gural
A
A
Shafran-Tikva
S
S
Ben-Neriah
S
S
Ben-Yehuda
D
D
D048868:Adaptor Proteins, Signal Transducing; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002352:Carrier Proteins; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D019450:Genes, MDR; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D007621:Karyotyping; D007938:Leukemia / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012189:Retrospective Studies; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D000070957:MutL Protein Homolog 1