Drug treatment in the development of mismatch repair defective acute leukemia and myelodysplastic syndrome.
DNA from therapy-related acute leukemia/myelodysplastic syndrome cases (tAL/MDS) from the GIMEMA [Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto] Archive was examined for the microsatellite instability (MSI(+)) phenotype that is diagnostic for defective DNA mismatch repair. More than 60% (16/25) of tAL/MDS cases were MSI(+) in contrast to <4% (0/28) of de novo cases. hMLH1 gene silencing was rare and evidence of promoter methylation was found in less than one-third of the MSI(+) cases. Among the GIMEMA patients who had been treated for breast cancer there was an apparent trend towards early onset primary breast disease. This suggests that there might be common predisposing factors for breast cancer and tAL/MDS. There were also three examples of mutations in the MRE11 gene among the 25 tAL/MDS cases suggesting that defective recombinational DNA repair may promote the development of secondary malignancy. MSI(+) tAL/MDS was significantly associated with previous chemotherapy and the frequency of MSI(+) among radiotherapy patients was considerably lower. In view of the established relationship between drug resistance and mismatch repair defects, we suggest that selection for therapeutic drug resistance may contribute to the incidence of MSI(+) tAL/MDS.
Casorelli
Ida
I
Istituto Superiore di Sanita', Laboratorio di Tossicologia Comparata, Rome, Italy.
Offman
Judith
J
Mele
Luca
L
Pagano
Livio
L
Sica
Simona
S
D'Errico
Mariarosaria
M
Giannini
Giuseppe
G
Leone
Giuseppe
G
Bignami
Margherita
M
Karran
Peter
P
D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000367:Age Factors; D000368:Aged; D020137:Base Pair Mismatch; D001854:Bone Marrow Cells; D001943:Breast Neoplasms / Q000235:genetics; D002352:Carrier Proteins; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D043243:DNA Sequence, Unstable; D005091:Exons; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D004247:DNA; D000070957:MutL Protein Homolog 1