title: Genomic abnormalities in chronic lymphocytic leukemia influence gene expression by a gene dosage effect.
abstract: This work describes the identification and impact of somatic genomic abnormalities in human chronic lymphocytic leukemia (CLL). Using molecular cytogenetics (FISH) and G-banding cytogenetic analysis, chromosome abnormalities were detected in 37 of 46 (80.4%) CLL patients. 13q14 deletion was the most common finding followed by trisomy 12 and 11q22.3 deletion. 17p13 deletion was also detected as were several less frequent chromosome abnormalities. The presence of these abnormalities significantly influenced the period of treatment-free survival as well as other clinical characteristics. In particular, CLL samples with trisomy 12 and 11q22.3 deletion were associated with shorter treatment-free survival. In order to identify the under-lying molecular differences among CLL subgroups with different chromosome abnormalities, gene expression profiling was performed on a custom DNA microarray consisting of 10,000 human gene-specific oligonucleotides. A gene dosage effect was observed where the expression of genes at the genetic loci of the sites of the somatic genomic abnormality was altered in a fashion according to the type of genomic change. This phenomenon was particularly evident in CLL samples with trisomy 12 and 17p13 deletion. Thus, this study demonstrates that genomic abnormalities influence gene expression in CLL by a dosage effect.
authors.affiliation: Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-6395, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Dickinson
authors.forename: Avadhut
authors.initials: A
authors.lastname: Joshi
authors.forename: Javeed
authors.initials: J
authors.lastname: Iqbal
authors.forename: Warren
authors.initials: W
authors.lastname: Sanger
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bierman
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016019:Survival Analysis; D014314:Trisomy