Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia
| Autor: | Julie Irving, Vikki Rand, Jonathan C. Strefford, Sarra Ryan, Hannah M. Ensor, Dino Masic, Helen Parker, Lisa J. Russell, Hazel M. Robinson, Lynne Minto, Paul Sinclair, Anthony V. Moorman, Lisa Jones, Heather Morrison, Claire Schwab, Christine J. Harrison |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Adolescent Chromosomes Human Pair 21 Immunology Gene Dosage Biology medicine.disease_cause Biochemistry Cohort Studies Young Adult CDKN2A Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Acute lymphocytic leukemia medicine Humans Child Gene Janus Kinases Chromosome Aberrations Genetics Mutation Chromosome Cancer Cell Biology Hematology medicine.disease ETV6 Child Preschool Core Binding Factor Alpha 2 Subunit Female Chromosome 21 |
| Zdroj: | Blood. 117:6848-6855 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2011-01-329961 |
| Popis: | Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) that has a dismal outcome when treated with standard therapy. For improved diagnosis and risk stratification, the initiating genetic events need to be elucidated. To investigate the genetic basis of BCP-ALL, genomes of 94 iAMP21 patients were interrogated by arrays, FISH, and multiplex ligation-dependent probe amplification. Most copy number alterations targeted chromosome 21, reinforcing the complexity of this chromosome. The common region of amplification on chromosome 21 was refined to a 5.1-mb region that included RUNX1, miR-802, and genes mapping to the Down syndrome critical region. Recurrent abnormalities affecting genes in key pathways were identified: IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%), and RB1 (37%). Investigation of clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 rearrangements. Patient outcome was uniformly poor with standard therapy irrespective of the presence or absence of these changes. This study has provided evidence that chromosome 21 instability is the only anomaly among those so far investigated that is common to all iAMP21 patients, and therefore the initiating event is likely to be found among the complex structural rearrangements of this abnormal chromosome. |
| Databáze: | OpenAIRE |
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