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Human Molecular Genetics Advance Access published online on September 26, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm273
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma

Patrick J. Hayden1,{dagger}, Prerna Tewari1,{dagger}, Derek W. Morris2, Anthony Staines3, Dominique Crowley3, Alexandra Nieters4, Nikolaus Becker4, Silvia de Sanjosé5, Lenka Foretova6, Marc Maynadié7, Pier Luigi Cocco8, Paolo Boffetta9, Paul Brennan9, Stephen J Chanock10, Paul V Browne1 and Mark Lawler1,*

1 Durkan Leukaemia Laboratories, Department of Haematology and Institute of Molecular Medicine, Trinity College Dublin, Ireland 2 Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Ireland 3 School of Public Health and Population Science, University College Dublin, Ireland 4 Divison of Epidemiology, German Cancer Research Center, Heidelberg, Germany 5 Epidemiology, Municipal Institute of Medical Research, Barcelona, Spain 6 Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic 7 Unit of Biological Haematology,Haematology, Dijon University Hospital,Dijon, France 8 Institute of Occupational Medicine, University of Cagliari, Cagliari, Italy 9 International Agency for Research on Cancer, Lyon, France 10 Core Genotyping Facility, Advanced Technology Corp, National Cancer Institute Gaithersburg, Maryland NIH, US

* Address for correspondence: Professor Mark Lawler, Durkan Leukaemia Laboratories, Institute of Molecular Medicine, Trinity Centre, St James's Hospital, Dublin 8, Ireland Telephone: 353 1 896 2093 Fax: 353 1 4103476 E-mail: emplawler{at}tcd.ie, mlawler{at}stjames.ie

Received July 17, 2007; Revised September 14, 2007; Accepted September 14, 2007

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 3 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% vs 80.8%; odds ratio (OR) 1.51; 95% confidence interval (CI) 1.10-2.08; P = 0.0133), as was the AA genotype (74% vs 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 1 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.

{dagger} The first two authors should be regarded as joint first authors.


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