Clinical utility of array comparative genomic hybridization for detection of chromosomal abnormalities in pediatric acute lymphoblastic leukemia

Abstract

Background: Accurate detection of recurrent chromosomal abnormalities is critical to assign patients to risk-based therapeutic regimens for pediatric acute lymphoblastic leukemia (ALL).

Procedure: We investigated the utility of array comparative genomic hybridization (aCGH) for detection of chromosomal abnormalities compared to standard clinical evaluation with karyotype and fluorescent in situ hybridization (FISH). Fifty pediatric ALL diagnostic bone marrows were analyzed by bacterial artificial chromosome (BAC) array and findings compared to standard clinical evaluation.

Results: Sensitivity of aCGH was 79% to detect karyotypic findings other than balanced translocations, which cannot be detected by aCGH because they involve no copy number change. aCGH also missed abnormalities occurring in subclones constituting less than 25% of cells. aCGH detected 44 additional abnormalities undetected or misidentified by karyotype with 21 subsequently validated by FISH, including abnormalities in 4 of 10 cases with uninformative cytogenetics. aCGH detected concurrent terminal deletions of both 9p and 20q in three cases, in two of which the 20q deletion was undetected by karyotype. A narrow region of loss at 7p21 was detected in two cases.

Conclusions: aCGH detects the majority of karyotypic findings other than balanced translocations, and may provide key prognostic information in the approximately 35% of cases with uninformative cytogenetics.

Figure 1

aCGH can correct misidentification of chromosome morphology by karyotype. A: Karyotype for case 69 indicated high hyperdiploidy including trisomy 14. B: aCGH findings were concordant except for detection of trisomy 18, and no trisomy 14. C: Subsequent FISH testing confirmed presence of two copies of chromosome 14 (using a two-color 14q34 IgH break-apart probe) and three copies of chromosome 18 (using a chromosome 18 centromeric probe).

Figure 2

Location of the bacterial artificial chromosome (BAC) clones covering the breakpoints on chromosomes 9 and 20 in cases 29, 73, and 86 (based on information from the UCSC Human Genome Browser, March 2006 assembly, at http://genome.ucsc.edu/cgibin/hgGateway).