Microsatellite analysis in childhood acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVE Genetic alterations, including genomic instability, represent possible steps towards a malignant transformation. One approach to delineate replication errors in cancer cells is to determine alterations of microsatellites that are short tandem repeat sequences dispersed throughout the human genome. We have investigated whether genomic instability may be a possible event in the leukemogenic process by evaluating the pattern of instability in 41 cases of childhood acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS Eighty-two samples of genomic DNA (41 at diagnosis and 41 at remission) were analyzed by PCR with microsatellite markers chosen on five different chromosomes (2, 10, 11, 13, 18) known to be frequently involved in tumors of various origins. Since deletions of the short arm of chromosome 12 are relatively common in children with ALL, we also analyzed one region flanked by the microsatellite marker D12S308 on 12p. This area encompasses a genetic locus which contains the putative suppressor gene KIP1. RESULTS A pattern of MI at one or two loci on different chromosomes could be documented in 4 of the 41 cases analyzed (9.7%). Three were common ALL and 1 was a T-ALL. One case showed two concomitant sites of instability, while 1 revealed two additional bands by using simultaneously microsatellite markers D2S123 and D18S58. INTERPRETATION AND CONCLUSIONS These results indicate that genetic instability of microsatellite repeat sequences occurs in a proportion of childhood ALL. Mismatched repair errors documented in hereditary and sporadic solid tumors may thus be involved in hematological malignancies. While in such cases the pattern of genomic instability appears indicative of a mutator phenotype and of a potential predisposition towards a leukemic transformation, other genomic loci close to cytogenetic and molecular alterations known to occur in ALL need to be investigated in depth in cases with an apparently non mutated phenotype.

[1]  R. Foà,et al.  Microsatellite instability is associated with the histological features of the tumor in nonfamilial colorectal cancer. , 1996, Cancer research.

[2]  S. Ben-Neriah,et al.  Microsatellite instability and p53 mutations in therapy-related leukemia suggest mutator phenotype. , 1996, Blood.

[3]  P. Marynen,et al.  Biallelic alterations of both ETV6 and CDKN1B genes in a t(12;21) childhood acute lymphoblastic leukemia case. , 1996, Cancer research.

[4]  S. Bohlander,et al.  Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in childhood acute lymphoblastic leukemia. , 1996, Cancer research.

[5]  J. Weissenbach,et al.  Loss of heterozygosity in the chromosomal region 12p12-13 is very common in childhood acute lymphoblastic leukemia and permits the precise localization of a tumor-suppressor gene distinct from p27KIP1. , 1995, Blood.

[6]  L. Chieco‐Bianchi,et al.  Genetic instability of a dinucleotide repeat-rich region in three hematologic malignancies. , 1995, Leukemia.

[7]  James M. Roberts,et al.  TEL and KIP1 define the smallest region of deletions on 12p13 in hematopoietic malignancies. , 1995, Blood.

[8]  C. Reynolds,et al.  Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood. , 1995, Blood.

[9]  J. Benítez,et al.  Genetic instability of microsatellites in hematological neoplasms. , 1995, Leukemia.

[10]  E. Porfiri.  DCC (deleted in colorectal cancer) inactivation in hematological malignancies. , 1995, Leukemia & lymphoma.

[11]  K. Mills,et al.  No evidence for microsatellite instability or consistent loss of heterozygosity at selected loci in chronic myeloid leukaemia blast crisis. , 1994, Leukemia.

[12]  L. Loeb.  Microsatellite Instability: Marker of a Mutator Phenotype in Cancer , 1994 .

[13]  R. Fleischmann,et al.  Mutations of two P/WS homologues in hereditary nonpolyposis colon cancer , 1994, Nature.

[14]  C. Wada,et al.  Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia. , 1994, Blood.

[15]  Cécile Fizames,et al.  The 1993–94 Généthon human genetic linkage map , 1994, Nature Genetics.

[16]  J. Siegfried,et al.  Genetic instability of microsatellite sequences in many non-small cell lung carcinomas. , 1994, Cancer research.

[17]  R. Fleischmann,et al.  Mutation of a mutL homolog in hereditary colon cancer. , 1994, Science.

[18]  D. Ward,et al.  Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer , 1994, Nature.

[19]  Bert Vogelstein,et al.  Hypermutability and mismatch repair deficiency in RER+ tumor cells , 1993, Cell.

[20]  L. Aaltonen,et al.  Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. , 1993, Cancer research.

[21]  N. Copeland,et al.  The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer , 1993, Cell.

[22]  G. Hübner,et al.  Monitoring of relapse and remission in acute leukaemias by DNA‐fingerprint analysis , 1993, British journal of haematology.

[23]  Tomas A. Prolla,et al.  Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair , 1993, Nature.

[24]  K. Miyake,et al.  Alterations in the deleted in colorectal carcinoma gene in human primary leukemia. , 1993, Blood.

[25]  K. Kinzler,et al.  Clues to the pathogenesis of familial colorectal cancer. , 1993, Science.

[26]  B. Vogelstein,et al.  A genetic model for colorectal tumorigenesis , 1990, Cell.

[27]  Kathleen R. Cho,et al.  Identification of a chromosome 18q gene that is altered in colorectal cancers. , 1990, Science.

[28]  D. Sidransky,et al.  Mutator phenotype in a subset of chronic lymphocytic leukemia. , 1996, Blood.

[29]  M. Fey,et al.  Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias. , 1996, Blood.

[30]  M. Stratton,et al.  Instability of short tandem repeats (microsatellites) in human cancers , 1994, Nature Genetics.

[31]  S. Raimondi,et al.  Current status of cytogenetic research in childhood acute lymphoblastic leukemia. , 1993, Blood.

[32]  J. Hancock,et al.  DCC tumor suppressor gene is inactivated in hematologic malignancies showing monosomy 18. , 1993, Blood.