Repeated sequences in CASPASE-5 and FANCD2 but not NF1 are targets for mutation in microsatellite-unstable acute leukemia/myelodysplastic syndrome

TY - JOUR

T1 - Repeated sequences in CASPASE-5 and FANCD2 but not NF1 are targets for mutation in microsatellite-unstable acute leukemia/myelodysplastic syndrome

AU - Offman, Judith

AU - Gascoigne, Karen

AU - Bristow, Fiona

AU - Macpherson, Peter

AU - Bignami, Margherita

AU - Casorelli, Ida

AU - Leone, Giuseppe

AU - Pagano, Livio

AU - Sica, Simona

AU - Halil, Ozay

AU - Cummins, David

AU - Banner, Nicholas R

AU - Karran, Peter

PY - 2005/5

Y1 - 2005/5

N2 - 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.

AB - 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.

KW - Alleles

KW - Caspases/genetics

KW - Cell Line, Tumor

KW - Genotype

KW - Humans

KW - Leukemia, Myeloid, Acute/genetics

KW - Microsatellite Repeats/genetics

KW - Mutagenesis/genetics

KW - Myelodysplastic Syndromes/genetics

KW - Neurofibromin 1/genetics

U2 - 10.1158/1541-7786.MCR-04-0182

DO - 10.1158/1541-7786.MCR-04-0182

M3 - Article

C2 - 15886296

SN - 1541-7786

VL - 3

SP - 251

EP - 260

JO - MOLECULAR CANCER RESEARCH

JF - MOLECULAR CANCER RESEARCH

IS - 5

ER -