Genomic profiling of pediatric ALK-positive anaplastic large cell lymphoma: a Children's Cancer and Leukaemia Group Study.
Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a T-cell malignancy in which ALK expression is a consequence of the t(2;5) or a variant translocation involving Chromosome 2. For the most part, this disease presents in the pediatric population and most, but not all, patients are successfully treated. Although the t(2;5) product nucleophosmin-ALK has been extensively studied for its transforming properties, very little is known regarding cooperative genetic mutations that may contribute to lymphomagenesis and may predict survival outcome, specifically in a purely pediatric population. We set out to determine the frequency and positions of genomic imbalances in this relatively rare disease. We collected biopsy material from 15 UK-resident children with ALK-expressing ALCL. We performed array comparative genomic hybridization at a resolution of 1 MB using DNA isolated from tumor tissue. Some of the more common genomic gains were confirmed by quantitative PCR. Regions of genomic gain were far more common than losses and were most often detected on chromosomes 1-4, 5-12, 14, and 17, with Chromosome 11 being the most frequent site of genomic imbalances. Patients with 14 or fewer imbalances had a lower overall 3-year survival (87.5-40%, P = 0.14) as did patients with gains in the regions of DDB1 or BIRC5. A range of genomic imbalances exist in ALK-expressing ALCL of a pediatric origin, with a greater number associated with poorer overall survival.
Youssif
Catrin
C
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
Goldenbogen
Jan
J
Hamoudi
Rifat
R
Carreras
Joaquim
J
Viskaduraki
Maria
M
Cui
Yu-xin
YX
Bacon
Chris M
CM
Burke
G A Amos
GA
Turner
Suzanne D
SD
D000293:Adolescent; D000077548:Anaplastic Lymphoma Kinase; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics; D017353:Gene Deletion; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D053208:Kaplan-Meier Estimate; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology* / Q000235:genetics*; D008390:Markov Chains; D008869:Microtubule-Associated Proteins / Q000235:genetics; D016254:Mutagenesis, Insertional; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases; D015203:Reproducibility of Results; D018709:Statistics, Nonparametric; D000077022:Survivin
C107489:BIRC5 protein, human; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases