Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias

Abstract

Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.

DHFR and MSH3 co-amplification in childhood acute lymphoblastic leukaemia, in vitro and in vivo

“…A number of studies have assessed the incidence of MMR defects in haematological malignancies (19,(23)(24)(25)(26)(27)(28)(29)(30). However, although we and others have found a surprisingly high incidence of MMR defects in leukaemic cell lines (19,31,32), with the exception of therapyrelated leukaemias (33), the incidence in de novo leukaemias is rare.…”

Expression and prognostic roles of PABPC1 in esophageal cancer: Correlation with tumor progression and postoperative survival

“…PABPC1 is located at chromosome region 8q22.2-23. Loss of heterozygosity (LOH) at 8q22 has been reported in human malignancies, such as oral cancer (21), breast cancer (22) and leukemia (23), and proposes the existence of a tumor suppressor gene in various cancers. It is speculated that the inactivation of PABPC1 may be involved in the carcinogenesis of those organs.…”

Microsatellite instability and clonal heterogeneity of MDR1 messenger RNA expression in trimetrexate-resistant human leukemia molt-3 cells developed in thymidine

“…Compared with solid tumors, microsatellite instability in leukemic cells is rare (Sill et al, 1996; Pabst et al, 1996). It is, however, conceivable that standard PCR‐based assays for microsatellite polymorphisms are not sensitive enough to detect instability of polymorphic microsatellites reproducibly in uncloned and heterogeneous population of leukemic cells from bulk patient materials.…”

“…Compared with solid tumors, microsatellite instability in leukemia cells is rare (Wada et al, 1994; Ben‐Yehuda et al, 1996; Sill et al, 1996), and it is largely unknown how much genomic instability is involved in the molecular pathogenesis of leukemia. Multistep accumulation of somatic mutations, particularly on top of specific chromosomal translocations, governs the molecular pathogenesis of leukemia (Pabst et al, 1996). Further genetic changes are required to confer resistant properties to chemotherapeutic agents to leukemic cells (Borst, 1991; Chabner et al, 1994).…”