Increased risk for therapy-associated hematologic malignancies in patients with carcinoma of the breast and combined homozygous gene deletions of glutathione transferases M1 and T1.
The most serious long-term complications of anti-tumor therapy are secondary malignancies. Parameters which might allow an estimation of the individual risk to develop a therapy-induced neoplasia are urgently needed. We examined whether the genotypes of the glutathione S-transferases (GST) M1 and T1, which metabolize various cytostatic drugs, as well as reactive oxygen species, influence the risk for secondary neoplasia. In a retrospective study, we analyzed peripheral blood lymphocyte or bone marrow DNA samples from 213 patients with acute myeloid leukemia (AML) and 128 with myelodysplastic syndromes (MDS) 44 of whom suffered from therapy-associated AML/MDS. The control group consisted of 239 healthy individuals with comparable composition as to race and sex. GSTM1 and GSTT1 were analyzed by multiplex PCR. Comparison between patients and control group revealed a significant (P=0.0003) overrepresentation of combined deletions of both GSTM1 and GSTT1 (double null genotype) in the group of patients with AML/MDS secondary to chemo- and/or radiotherapy of a carcinoma of the breast. In this group, 55% of the patients displayed the double null genotype as compared with 8.8% in the control group. We conclude that patients with carcinoma of the breast and inheritance of a combined gene deletion of GSTM1 and GSTT1 might bear an increased risk to develop a secondary therapy-induced hematologic neoplasia. An insufficient detoxification of cytostatic drugs such as cyclophosphamide is suggested to represent the underlying pathomechanism.
Haase
Detlef
D
Department of Hematology and Oncology, Georg-August-University, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. haase-bovenden@t-online.de
Binder
Claudia
C
Bünger
Jürgen
J
Fonatsch
Christa
C
Streubel
Berthold
B
Schnittger
Susanne
S
Griesinger
Frank
F
Westphal
Götz
G
Schoch
Claudia
C
Knopp
Agnes
A
Berkovicz
Dinko
D
Krieger
Otto
O
Wörmann
Bernhard
B
Hilgers
Reinhard
R
Hallier
Ernst
E
Schulz
Thomas
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001854:Bone Marrow Cells / Q000201:enzymology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D018567:Breast Neoplasms, Male / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D002869:Chromosome Aberrations; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000209:etiology / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced / Q000209:etiology / Q000235:genetics; D007953:Leukemia, Radiation-Induced / Q000209:etiology; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000139:chemically induced / Q000209:etiology / Q000235:genetics; D011878:Radiotherapy / Q000009:adverse effects; D012189:Retrospective Studies; D012307:Risk Factors; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1