title: Repeated sequences in CASPASE-5 and FANCD2 but not NF1 are targets for mutation in microsatellite-unstable acute leukemia/myelodysplastic syndrome.
abstract: 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.
authors.affiliation: Cancer Research UK London Research Institute, Mammalian DNA Repair Laboratory, Clare Hall Laboratories, South Mimms, Herts, United Kingdom EN6 3LD.
authors.forename: Judith
authors.initials: J
authors.lastname: Offman
authors.forename: Karen
authors.initials: K
authors.lastname: Gascoigne
authors.forename: Fiona
authors.initials: F
authors.lastname: Bristow
authors.forename: Peter
authors.initials: P
authors.lastname: Macpherson
authors.forename: Margherita
authors.initials: M
authors.lastname: Bignami
authors.forename: Ida
authors.initials: I
authors.lastname: Casorelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Leone
authors.forename: Livio
authors.initials: L
authors.lastname: Pagano
authors.forename: Simona
authors.initials: S
authors.lastname: Sica
authors.forename: Ozay
authors.initials: O
authors.lastname: Halil
authors.forename: David
authors.initials: D
authors.lastname: Cummins
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Banner
authors.forename: Peter
authors.initials: P
authors.lastname: Karran
mesh_terms: 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
chemical_list: D025542:Neurofibromin 1; C099217:CASP5 protein, human; D020169:Caspases