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Integrated Genomic Analysis Implicates Haploinsufficiency of Multiple Chromosome 5q31.2 Genes in De Novo Myelodysplastic Syndromes Pathogenesis
- Source :
- PLoS ONE, PLoS ONE, Vol 4, Iss 2, p e4583 (2009)
- Publication Year :
- 2009
- Publisher :
- Public Library of Science (PLoS), 2009.
-
Abstract
- Deletions spanning chromosome 5q31.2 are among the most common recurring cytogenetic abnormalities detectable in myelodysplastic syndromes (MDS). Prior genomic studies have suggested that haploinsufficiency of multiple 5q31.2 genes may contribute to MDS pathogenesis. However, this hypothesis has never been formally tested. Therefore, we designed this study to systematically and comprehensively evaluate all 28 chromosome 5q31.2 genes and directly test whether haploinsufficiency of a single 5q31.2 gene may result from a heterozygous nucleotide mutation or microdeletion. We selected paired tumor (bone marrow) and germline (skin) DNA samples from 46 de novo MDS patients (37 without a cytogenetic 5q31.2 deletion) and performed total exonic gene resequencing (479 amplicons) and array comparative genomic hybridization (CGH). We found no somatic nucleotide changes in the 46 MDS samples, and no cytogenetically silent 5q31.2 deletions in 20/20 samples analyzed by array CGH. Twelve novel single nucleotide polymorphisms were discovered. The mRNA levels of 7 genes in the commonly deleted interval were reduced by 50% in CD34+ cells from del(5q) MDS samples, and no gene showed complete loss of expression. Taken together, these data show that small deletions and/or point mutations in individual 5q31.2 genes are not common events in MDS, and implicate haploinsufficiency of multiple genes as the relevant genetic consequence of this common deletion.
- Subjects :
- Heterozygote
medicine.medical_specialty
lcsh:Medicine
Single-nucleotide polymorphism
Biology
medicine.disease_cause
Polymorphism, Single Nucleotide
03 medical and health sciences
0302 clinical medicine
Bone Marrow
Molecular genetics
medicine
Humans
lcsh:Science
Genetics and Genomics/Cancer Genetics
Genetics and Genomics/Genetics of Disease
Skin
030304 developmental biology
Genetics
Comparative Genomic Hybridization
0303 health sciences
Mutation
Multidisciplinary
Point mutation
lcsh:R
Cytogenetics
De novo Myelodysplastic Syndrome
Hematology/Myelodysplastic Syndrome and Bone Marrow Failure
Molecular biology
3. Good health
Genetics and Genomics/Chromosome Biology
Genetics and Genomics/Genome Projects
Myelodysplastic Syndromes
030220 oncology & carcinogenesis
Chromosomes, Human, Pair 5
lcsh:Q
Chromosome Deletion
Haploinsufficiency
Genes, Neoplasm
Research Article
Comparative genomic hybridization
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....9002727163123319b3fd8c6fe32bc7dc