Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia.
We conducted a large-scale association study to identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), analyzing 992 patients and 2707 healthy controls. To increase the likelihood of identifying disease-causing alleles we genotyped 1467 coding nonsynonymous single nucleotide polymorphisms (nsSNPs) in 865 candidate cancer genes, biasing nsSNP selection toward those predicted to be deleterious. Preeminent associations were identified in SNPs mapping to genes pivotal in the DNA damage-response and cell-cycle pathways, including ATM F858L (odds ratio [OR] = 2.28, P < .0001) and P1054R (OR = 1.68, P = .0006), CHEK2 I157T (OR = 14.83, P = .0008), BRCA2 N372H (OR = 1.45, P = .0032), and BUB1B Q349R (OR = 1.42, P = .0038). Our findings implicate variants in the ATM-BRCA2-CHEK2 DNA damage-response axis with risk of CLL.
Rudd
Matthew F
MF
Sections of Cancer Genetics and Haemato-Oncology, Institute of Cancer Research, Sutton, Surrey, UK.
Sellick
Gabrielle S
GS
Webb
Emily L
EL
Catovsky
Daniel
D
Houlston
Richard S
RS
D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D024682:BRCA2 Protein / Q000235:genetics*; D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases