Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia

• Published in: Blood Vol. 108; no. 2; pp. 638 - 644
• Main Authors: Rudd, Matthew F., Sellick, Gabrielle S., Webb, Emily L., Catovsky, Daniel, Houlston, Richard S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.07.2006
• Subjects: Aged; Ataxia Telangiectasia Mutated Proteins; BRCA2 Protein - genetics; Case-Control Studies; Cell Cycle - genetics; Cell Cycle Proteins - genetics; Checkpoint Kinase 2; DNA Damage - genetics; DNA Repair - genetics; DNA-Binding Proteins - genetics; Female; Genetic Predisposition to Disease; Genotype; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - etiology; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Male; Middle Aged; Polymorphism, Single Nucleotide - genetics; Polymorphism, Single Nucleotide - physiology; Protein-Serine-Threonine Kinases - genetics; Tumor Suppressor Proteins - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-12-5022

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.