title: 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.
abstract: 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.
authors.affiliation: Department of Hematology and Oncology, Georg-August-University, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. haase-bovenden@t-online.de
authors.forename: Detlef
authors.initials: D
authors.lastname: Haase
authors.forename: Claudia
authors.initials: C
authors.lastname: Binder
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bünger
authors.forename: Christa
authors.initials: C
authors.lastname: Fonatsch
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Frank
authors.initials: F
authors.lastname: Griesinger
authors.forename: Götz
authors.initials: G
authors.lastname: Westphal
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
authors.forename: Agnes
authors.initials: A
authors.lastname: Knopp
authors.forename: Dinko
authors.initials: D
authors.lastname: Berkovicz
authors.forename: Otto
authors.initials: O
authors.lastname: Krieger
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wörmann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hilgers
authors.forename: Ernst
authors.initials: E
authors.lastname: Hallier
authors.forename: Thomas
authors.initials: T
authors.lastname: Schulz
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1