title: Structural genome variations in individuals with childhood cancer and tumour predisposition syndromes.
abstract: BACKGROUND
  Previous studies have shown a high prevalence of syndromes in children with cancer. We described four patterns of co-occurring morphological abnormalities indicating new tumour predisposition syndromes. These patterns were named after their key-abnormalities: blepharophimosis (BP), epicanthal folds (EF), asymmetric lower limbs (LLA) and Sydney creases (SC) pattern. The purpose of our study was to identify structural genomic variants possibly involved in these tumour predisposition syndromes.
  
  
  METHODS
  In 49 probands (13 from BP, nine from EF, 20 from LLA and seven from SC patterns respectively) karyotyping was performed. Copy number variation (CNV) in genomic DNA of the probands was analysed to detect microdeletions/-duplications using SNP array. FISH and quantitative-polymerase chain reaction (q-PCR) experiments were done to validate events identified by cytogenetic and CNV analysis.
  
  
  RESULTS
  Cytogenetic analysis showed an inherited inversion of chromosome 15, inv(15) (q25q26) in a proband with LLA-pattern. Evaluation of the genes at the breakpoints made it unlikely that these explained the phenotype and tumour in this patient. Eleven CNV events met our inclusion criteria; three inherited CNV events involved an oncogene. A duplication involving BCL9 was identified in a proband diagnosed with Burkitt lymphoma. A duplication involving PCM1 was identified in a proband diagnosed with pre-B-ALL. Both probands showed the EF-pattern of morphological abnormalities. A deletion involving TRA@ was identified in two probands from the BP-pattern diagnosed with rhabdomyosarcoma and pre-B-ALL respectively.
  
  
  CONCLUSIONS
  We report on structural genomic variants in paediatric cancer patients with newly recognised tumour predisposition syndromes. We identify three CNV events which we suggest to be susceptibility loci.
authors.affiliation: Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: saskia.hopman@amc.uva.nl.
authors.forename: Saskia
authors.initials: S
authors.lastname: Hopman
authors.affiliation: Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Merks
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Hubertus
authors.initials: H
authors.lastname: Eussen
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Hannie
authors.initials: H
authors.lastname: Douben
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Snijder
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands; Departments of Paediatrics, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
authors.affiliation: Department of Paediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Huib
authors.initials: H
authors.lastname: Caron
mesh_terms: D002648:Child; D007446:Chromosome Inversion / Q000235:genetics; D000013:Congenital Abnormalities / Q000235:genetics*; D020440:Gene Duplication / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D059785:Karyotype; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013577:Syndrome