Repeated sequences in CASPASE-5 and FANCD2 but not NF1 are targets for mutation in microsatellite-unstable acute leukemia/myelodysplastic syndrome.
Microsatellite instability (MSI) in tumors is diagnostic for inactive DNA mismatch repair. It is widespread among some tumor types, such as colorectal or endometrial carcinoma, but is rarely found in leukemia. Therapy-related acute myeloid leukemia/myelodysplastic syndrome (tAML/MDS) is an exception, and MSI is frequent in tAML/MDS following cancer chemotherapy or organ transplantation. The development of MSI+ tumors is associated with an accumulation of insertion/deletion mutations in repetitive sequences. These events can cause inactivating frameshifts or loss of expression of key growth control proteins. We examined established MSI+ cell lines and tAML/MDS cases for frameshift-like mutations of repetitive sequences in several genes that have known, or suspected, relevance to leukemia. CASPASE-5, an acknowledged frameshift target in MSI+ gastrointestinal tract tumors, was frequently mutated in MSI+ cell lines (67%) and in tAML/MDS (29%). Frameshift-like mutations were also observed in the NF1 and FANCD2 genes that are associated with genetic conditions conferring a predisposition to leukemia. Both genes were frequent targets for mutation in MSI+ cell lines and colorectal carcinomas. FANCD2 mutations were also common in MSI+ tAML/MDS, although NF1 mutations were not observed. A novel FANCD2 polymorphism was also identified.
Offman
Judith
J
Cancer Research UK London Research Institute, Mammalian DNA Repair Laboratory, Clare Hall Laboratories, South Mimms, Herts, United Kingdom EN6 3LD.
Gascoigne
Karen
K
Bristow
Fiona
F
Macpherson
Peter
P
Bignami
Margherita
M
Casorelli
Ida
I
Leone
Giuseppe
G
Pagano
Livio
L
Sica
Simona
S
Halil
Ozay
O
Cummins
David
D
Banner
Nicholas R
NR
Karran
Peter
P
D000483:Alleles; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D018895:Microsatellite Repeats / Q000235:genetics*; D016296:Mutagenesis / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics
D025542:Neurofibromin 1; C099217:CASP5 protein, human; D020169:Caspases