Loss of Heterozygosity in Childhood Acute Lymphoblastic Leukemia Detected by Genome-Wide Microarray Single Nucleotide Polymorphism Analysis

Abstract

Loss of heterozygosity (LOH) is detectable in many forms of malignancy, including leukemia, using techniques such as microsatellite analysis and comparative genomic hybridization. However, these techniques are laborious and require the use of relatively large amounts of DNA if the whole genome is to be examined. Here we describe the use of oligonucleotide microarrays to characterize single nucleotide polymorphisms (SNPs) in lymphoblasts isolated from children with acute lymphoblastic leukemia for the pan-genomic mapping of LOH with a resolution of 100 to 200 kb. Results were compared with DNA obtained during remission and on relapse. Abnormalities were seen in 8 of 10 cases. The two cases with no abnormalities and one case that showed identical changes at relapse and presentation remain in remission 1 to 9 years following retreatment. The remaining seven patients died following relapse. In four cases, LOH was only detectable at relapse suggesting that progressive LOH may be a cause of disease progression and/or drug resistance. This was supported by detailed analysis of one case in which LOH involving the glucocorticoid receptor was associated with mutation of the remaining allele. The most frequent abnormality detected involved chromosome 9p. In each of the four cases where this was observed LOH included the INK4 locus. In three of the four cases, INK4 loss was only observed at relapse, suggesting that this abnormality may be commonly associated with treatment failure. These observations show that SNP array analysis is a powerful new tool for the analysis of allelic imbalance in leukemic blasts.

Allelic alterations in well‐differentiated neuroendocrine tumors (carcinoid tumors) identified by genome‐wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors

“…The combination of both allelotyping and copy number analysis for each locus allowed us to identify one tumor with LOH of two chromosomes without copy number loss, suggesting uniparental disomy of chromosomes either due to nondisjunction event followed by chromosomal duplication or a recombination. These alterations have been reported in acute lymphoblastic leukemias (Irving et al, 2005;Raghavan et al, 2005) and PETs , and are common in nonseminomatous germ cell tumors (Lu et al, 2005). These alterations cannot be detected by methodology that utilizes chromosomal copy number alone, such as comparative genomic hybridization or in situ hybridization.…”

“…This method has been used to determine AI in patients with acute lymphoblastic and acute myeloid leukemias (Irving et al, 2005;Raghavan et al, 2005), and bladder and breast cancers (Hoque et al, 2003;Wang et al, 2004;Koed et al, 2005) and PETs . WDNTs from lung and gastrointestinal tract have less allelic alterations compared to other tumors that have been studied by SNP allelotyping, including PETs.…”

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

“…Irving et al 43 examined a small cohort of pediatric ALL cases (N ¼ 10) using SNP arrays examining 10 000 markers, and detected LOH in the majority of cases, most commonly involving CDKN2A/B at 9p21.3. This was one of the first studies to show that SNP arrays could successfully identify LOH in cancer, although the relatively low resolution of these arrays precluded precise delineation of many of the identified regions of genetic alteration.…”

Using high-throughput SNP technologies to study cancer

“…This approach has opened a whole new area of cancer research. Such studies have included the evaluation of basal cell carcinomas (Teh et al, 2005), Wilms' tumors (Yuan et al, 2005), ovarian tumors (Thompson et al, 2005), osteosarcomas , prostate cancer (Lieberfarb et al, 2003), small cell and nonsmall cell lung carcinomas Zhao et al, 2004;Ishikawa et al, 2005), breast cancer Herr et al, 2005), squamous cell carcinomas , bladder tumors (Koed et al, 2005), melanomas (Garraway et al, 2005), acute lymphoblastic leukemias (Irving et al, 2005), and acute myeloid leukemias . In nearly all of these cases, novel locations of allelic imbalance have been identified.…”