title: Space-Time Clustering of Childhood Leukemia: Evidence of an Association with ETV6-RUNX1 (TEL-AML1) Fusion.
abstract: BACKGROUND
  Many studies have observed space-time clustering of childhood leukemia (CL) yet few have attempted to elicit etiological clues from such clustering. We recently reported space-time clustering of CL around birth, and now aim to generate etiological hypotheses by comparing clustered and nonclustered cases. We also investigated whether the clustering resulted from many small aggregations of cases or from a few larger clusters.
  
  
  METHODS
  We identified cases of persons born and diagnosed between 1985 and 2014 at age 0-15 years from the Swiss Childhood Cancer Registry. We determined spatial and temporal lags that maximized evidence of clustering based on the Knox test and classified cases born within these lags from another case as clustered. Using logistic regression adjusted for child population density, we determined whether clustering status was associated with age at diagnosis, immunophenotype, cytogenetic subtype, perinatal and socioeconomic characteristics, and pollution sources.
  
  
  RESULTS
  Analyses included 1,282 cases of which 242 were clustered (born within 1 km and 2 years from another case). Of all investigated characteristics only the t(12;21)(p13;q22) translocation (resulting in ETV6-RUNX1 fusion) differed significantly in prevalence between clustered and nonclustered cases (40% and 25%, respectively; adjusted OR 2.54 [1.52-4.23]; p = 0.003). Spatio-temporal clustering was driven by an excess of aggregations of two or three children rather than by a few large clusters.
  
  
  CONCLUSIONS
  Our findings suggest ETV6-RUNX1 is associated with space-time clustering of CL and are consistent with an infection interacting with that oncogene in early life leading to clinical leukemia.
authors.affiliation: Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0001-5273-1954
authors.initials: C
authors.lastname: Kreis
authors.affiliation: Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Lupatsch
authors.affiliation: University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Niggli
authors.affiliation: Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Egger
authors.affiliation: Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.
authors.forename: Claudia E
authors.initials: CE
authors.lastname: Kuehni
authors.affiliation: Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.
authors.forename: Ben D
authors.initials: BD
authors.lastname: Spycher
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007938:Leukemia / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D013029:Space-Time Clustering; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein