Atypical Cytogenetic Findings Detected by Whole Genomic Microarray Analysis In Pediatric Acute Lymphoblastic Leukemia Cases

Abstract 4862

The most characteristic cytogenetic findings such as hyperdiploidy, Tel/AML1 translocation, MLL rearrangement, and Philadelphia chromosome translocation are often correlated well with the initial risk stratification in pediatric B-cell acute lymphoblastic leukemia (ALL) patients. However, additional genomic aberrations may change the course of the prognosis and treatment. Recent development of chromosomal microarray analysis (CMA) or array comparative genomic hybridization (aCGH) enables a much better detection of genomic imbalances than standard cytogenetics, which is helpful in establishing new treatment protocols and refining the current regiments. We report 6 pediatric B-cell ALL patients studied by standard cytogenetics and aCGH using 105K or 60K oligonucleotide microchip (Agilent Technologies). Case 1 was a 3 year-old female with hyperdiploidy and was considered to be at low risk with good prognosis. Array CGH confirmed hyperdiploidy and also revealed a 3.6 Mb deletion in 11q23.1-q23.2. The patient failed to achieve a complete remission with a standard induction chemotherapy and is now considered to have a higher risk disease. Her therapy has been intensified. Case 2 was 4 year-old female with a normal karyotype and a 23.9 Mb deletion in 11q21-q23.3 plus a deletion in 9p including the PAX5 gene detected by aCGH. The patient met standard risk group criteria at diagnosis. She rapidly achieved remission with standard induction chemotherapy. Case 3 was a 7 year-old male with a normal karyotype. Array CGH detected a 46 Mb deletion in 11q14.34-q25 plus a 54 Mb duplication in Xq22.1-q28. This patient was classified as having a high risk disease at diagnosis due to the treatment with corticosteroids prior to diagnosis. She responded rapidly to intensive induction chemotherapy and achieved a full remission within 4 weeks. All 3 cases above had a deletion in 11q and all of them ended up in standard-high risk group. The smallest overlapped region was 3.6 Mb encompassing 46 annotated genes, including PPP2R1B, SDHD and USP28 that are associated with neoplasia. Case 2 and 3 also shared a deletion of 143 genes including ATM gene. Case 3 also had a deletion of MLL oncogene. Case 4 was a 16 year-old male with a ring chromosome 10. Array CGH revealed a duplication of almost the entire chromosome 10 except for some small regions: neutral copy numbers in pericentric region; a 480 Kb deletion within 10q24.32 including the NFKB2 gene, a member of the NF-kappaB/Rel transcription factors family with important roles as a central regulator of growth, differentiation and apoptosis in hematopoietic cell lineages; a 5.5 Mb triplication from 10q25.3-q26.11. In addition, aCGH also detected a deletion in 9p including the PAX5 gene. The patient responded poorly to intensive induction therapy and his treatment was intensified according to an established protocol for very high risk patients, but a complete remission has never been achieved with residual disease consistently detected by flow cytometry and cytogenetics for the past year. Case 5 was a 6 year-old male with two reciprocal translocations: t(2;3)(p23;q21) and t(5;14)(q13;q32). Array CGH detected deletions at all the breakpoints including a 2.0 Mb in 2p, 440 Kb in 3q, 540 Kb in 5q, and 500 Kb in 14q. There were also multiple imbalances in 9p: a 200 Kb duplication including the JAK2 gene; a 1.6 Mb deletion including MLLT3 gene, a 920 Kb homozygous deletion including the CDNK2A gene. In addition, a 4.4 Mb deletion in 4q21.1-q21.22 and a 2.5 Mb deletion in 4q22.1 were also detected. The patient met standard risk goup criteria at diagnosis and responded rapidly to standard induction chemotherapy achieving a full remission in 4 weeks with no residual disease detected by flow cytometry or cytogenetics. Case 6 was a 3.5 year-old Down syndrome male with complex rearrangements: 47,Y,dup(X)(q25q28),der(2)t(2;17)(q37;q21),+21c[1]/48,idem,+14[8]/47,XY,+21c[11]. Array CGH confirmed the cytogenetic findings and detected no loss in 2q but a gain in 17q where genes ILF1, AXIN2, and TBX2 have been associated with neoplasia. The patient responded slowly to standard induction chemotherapy and had minimal bone marrow disease detectable by flow cytometry after 4 weeks of treatment. His therapy has been intensified. In summary, aCGH provides additional genomic information that may be helpful in understanding the leukemogenesis and in evaluating the prognosis and therapeutic approaches.