Determination of chromosomal structural changes in childhood acute lymphoblastic leukemia using high-density SNP arrays Free

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Chromosomal aberration is believed to play a key role in the etiology of childhood acute lymphoblastic leukemia (ALL). Recently microarray technology designed for screening of the whole genome single nucleotide polymorphism (SNP) on a single platform has been used to detect chromosomal copy number (CN) changes, deletion and loss of heterozygosity (LOH). We used GeneChip^® Human Mapping 10K and/or 50K Arrays to determine chromosomal imbalances in 83 presentation samples from children with ALL. Two had LOH affecting multiple whole chromosomes, indicating hypodiploidy. Two had multiple regions of LOH with no copy number change reflecting consanguinity. Of the remaining 79, 34 (43%) had LOH with reduced CN, indicating deletion and 12 (15%) had LOH with no CN change indicating probable segmental acquired isodisomy (AID). One or more abnormality was discovered in all chromosomes apart from 5, 18, 21 and 22. The chromosomes most frequently affected were chromosome 6 (1 whole chromosome AID, 3 partial AID, 9 interstitial deletions), 9 (4,2,9) and 12 (1,2,8). A common area of deletion affecting 6(q16.1-16.3) was found in 7 cases. A further 3 cases had partial or whole chromosome AID affecting the same region. Eight cases showed 9p deletion affecting 9p21.3-22.3. A further 2 cases showed partial and 4 whole chromosome AID affecting the same region which included the CDKN2A tumor-suppressor locus on chromosome band 9p21. This region encodes p16^INK4A, a negative regulator of cyclin-dependent kinases, and p14^ARF,an activator of TP53. Loss of 9p has been associated with a poor prognosis in childhood ALL and to be progressive in some cases at relapse. Seven cases demonstrated deletions affecting 12p13.1-13.2. In a further three cases there was partial or whole chromosome AID affecting the same region. The minimal region of loss included both the TEL (ETV6)and CDKN1B (p27^Kip1). Fluorescence in situ hybridization (FISH) analysis was performed to confirm the status of the p16^INK4A on 9p21 and both genes (TEL and CDKN1B) on 12p13. Eight cases with 9p21 deletion showed p16^INK4A homozygous and hemizygous deletion in 3 and 5 cases respectively. FISH analysis on 5 of the 6 cases with either partial or whole chromosome 9p AID confirmed that these cases had retained two copies of p16^INK4A. FISH results were also available on 6 of the 10 cases with 12p13 aberrations. Four cases had hemizygous deletion on both TEL and CDKN1B, and a further 2 cases had only hemizygous deletion on TEL with intact of CDKN1B. These findings showed the concordance results between SNP array and FISH analysis. Our results demonstrate that SNP arrays are a powerful tool for the mapping of allelic imbalance in patient samples which will be applicable to other malignancies. This application also shows that AID is a frequent cause of LOH which a previously under-reported phenomenon in lymphoid malignancies.