Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations.
Although childhood high hyperdiploid acute lymphoblastic leukemia is associated with a favorable outcome, 20% of patients still relapse. It is important to identify these patients already at diagnosis to ensure proper risk stratification. We have investigated 11 paired diagnostic and relapse samples with single nucleotide polymorphism array and mutation analyses of FLT3, KRAS, NRAS and PTPN11 in order to identify changes associated with relapse and to ascertain the genetic evolution patterns. Structural changes, mainly cryptic hemizygous deletions, were significantly more common at relapse (P<0.05). No single aberration was linked to relapse, but four deletions, involving IKZF1, PAX5, CDKN2A/B or AK3, were recurrent. On the basis of the genetic relationship between the paired samples, three groups were delineated: (1) identical genetic changes at diagnosis and relapse (2 of 11 cases), (2) clonal evolution with all changes at diagnosis being present at relapse (2 of 11) and (3) clonal evolution with some changes conserved, lost or gained (7 of 11), suggesting the presence of a preleukemic clone. This ancestral clone was characterized by numerical changes only, with structural changes and RTK-RAS mutations being secondary to the high hyperdiploid pattern.
Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden. josef.davidsson@med.lu.se
J
J
Davidsson
K
K
Paulsson
D
D
Lindgren
H
H
Lilljebjörn
T
T
Chaplin
E
E
Forestier
M K
MK
Andersen
A
A
Nordgren
R
R
Rosenquist
T
T
Fioretos
B D
BD
Young
B
B
Johansson
D000293:Adolescent; D005075:Biological Evolution; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002999:Clone Cells; D004171:Diploidy; D005260:Female; D020869:Gene Expression Profiling; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
D014408:Biomarkers, Tumor; D020794:Receptor Protein-Tyrosine Kinases