Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma.
Cytogenetic analysis in myeloma reveals marked chromosomal instability. Both widespread genomic alterations and evidence of aberrant class switch recombination, the physiological process that regulates maturation of the antibody response, implicate the DNA repair pathway in disease pathogenesis. We therefore assessed 27 SNPs in three genes (XRCC3, XRCC4 and XRCC5) central to DNA repair in patients with myeloma and controls from the EpiLymph study and from an Irish hospital registry (n = 306 cases, 263 controls). For the haplotype-tagging SNP (htSNP) rs963248 in XRCC4, Allele A was significantly more frequent in cases than in controls (86.4 versus 80.8%; odds ratio 1.51; 95% confidence interval 1.10-2.08; P = 0.0133), as was the AA genotype (74 versus 65%) (P = 0.026). Haplotype analysis was performed using Unphased for rs963248 in combination with additional SNPs in XRCC4. The strongest evidence of association came from the A-T haplotype from rs963248-rs2891980 (P = 0.008). For XRCC5, the genotype GG from rs1051685 was detected in 10 cases from different national populations but in only one control (P = 0.015). This SNP is located in the 3'-UTR of XRCC5. Overall, these data provide support for the hypothesis that common variation in the genes encoding DNA repair proteins contributes to susceptibility to myeloma.
Hayden
Patrick J
PJ
Durkan Leukaemia Laboratories, Department of Haematology, Institute of Molecular Medicine, Trinity College Dublin, Ireland.
Tewari
Prerna
P
Morris
Derek W
DW
Staines
Anthony
A
Crowley
Dominique
D
Nieters
Alexandra
A
Becker
Nikolaus
N
de Sanjosé
Silvia
S
Foretova
Lenka
L
Maynadié
Marc
M
Cocco
Pier Luigi
PL
Boffetta
Paolo
P
Brennan
Paul
P
Chanock
Stephen J
SJ
Browne
Paul V
PV
Lawler
Mark
M
D016022:Case-Control Studies; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D000072200:Ku Autoantigen; D009101:Multiple Myeloma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012042:Registries
D004268:DNA-Binding Proteins; C110901:X-ray repair cross complementing protein 3; C101467:XRCC4 protein, human; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen