title: High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome.
abstract: Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as <10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrent-dup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Sweden. catarina.lundin@med.lu.se
authors.forename: Catarina
authors.initials: C
authors.lastname: Lundin
authors.forename: Lars
authors.initials: L
authors.lastname: Hjorth
authors.forename: Mikael
authors.initials: M
authors.lastname: Behrendtz
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.forename: Lars
authors.initials: L
authors.lastname: Palmqvist
authors.forename: Mette Klarskov
authors.initials: MK
authors.lastname: Andersen
authors.forename: Andrea
authors.initials: A
authors.lastname: Biloglav
authors.forename: Erik
authors.initials: E
authors.lastname: Forestier
authors.forename: Kajsa
authors.initials: K
authors.lastname: Paulsson
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007951:Leukemia, Myeloid / Q000150:complications / Q000235:genetics; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins; C074086:BTG1 protein, human