title: ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele.
abstract: Ataxia telangiectasia patients, with constitutional bi-allelic ATM mutations, have a marked risk of lymphoid tumors and ATM mutation carriers have a smaller risk of cancer. Sporadic ATM mutations occur in 10-20% of chronic lymphocytic leukemia and are often associated with chromosome 11q deletions which cause loss of an ATM allele. The role of constitutional ATM mutations in the pathogenesis of chronic lymphocytic leukemia is unknown. Here we investigated the frequency of constitutional ATM mutations in either of two chronic lymphocytic leukemia cohorts, those with and without a chromosome 11q deletion. We found that in comparison to controls, constitutional pathogenic ATM mutations were increased in patients with chromosome 11q deletions (6 of 140 vs. 0 of 281, P = 0.001) but not in those without 11q deletions (2 of 178 vs. 0 of 281, P = 0.15). These results suggest that ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but rather influences rapid disease progression through ATM loss.
authors.affiliation: School of Cancer Sciences, University of Birmingham, University of Birmingham, Birmingham B15 2TT, UK. t.stankovic@bham.ac.uk
authors.forename: Anna
authors.initials: A
authors.lastname: Skowronska
authors.forename: Belinda
authors.initials: B
authors.lastname: Austen
authors.forename: Judith E
authors.initials: JE
authors.lastname: Powell
authors.forename: Victoria
authors.initials: V
authors.lastname: Weston
authors.forename: David G
authors.initials: DG
authors.lastname: Oscier
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.forename: Christopher
authors.initials: C
authors.lastname: Fegan
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Taylor
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
mesh_terms: D000368:Aged; D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D019656:Loss of Heterozygosity; D008875:Middle Aged; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
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