title: Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours.
abstract: BACKGROUND
  Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T.
  
  
  METHODS
  From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity.
  
  
  RESULTS
  In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype.
  
  
  CONCLUSIONS
  Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Reiman
authors.forename: V
authors.initials: V
authors.lastname: Srinivasan
authors.forename: G
authors.initials: G
authors.lastname: Barone
authors.forename: J I
authors.initials: JI
authors.lastname: Last
authors.forename: L L
authors.initials: LL
authors.lastname: Wootton
authors.forename: E G
authors.initials: EG
authors.lastname: Davies
authors.forename: M M
authors.initials: MM
authors.lastname: Verhagen
authors.forename: M A
authors.initials: MA
authors.lastname: Willemsen
authors.forename: C M
authors.initials: CM
authors.lastname: Weemaes
authors.forename: P J
authors.initials: PJ
authors.lastname: Byrd
authors.forename: L
authors.initials: L
authors.lastname: Izatt
authors.forename: D F
authors.initials: DF
authors.lastname: Easton
authors.forename: D J
authors.initials: DJ
authors.lastname: Thompson
authors.forename: A M
authors.initials: AM
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D000328:Adult; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001932:Brain Neoplasms / Q000201:enzymology / Q000517:prevention & control; D001943:Breast Neoplasms / Q000201:enzymology / Q000517:prevention & control; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000201:enzymology / Q000517:prevention & control; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology* / Q000517:prevention & control*; D009426:Netherlands; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D006113:United Kingdom; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases