Carcinogenesis Advance Access published online on July 8, 2006
Carcinogenesis, doi:10.1093/carcin/bgl114
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1 International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon, France
* To whom correspondence should be addressed. X-ray repair cross complementing 1 (XRCC1) is required for single-strand break repair in human cells and several polymorphisms in this gene have been implicated in cancer risk and clinical prognostic factors. We examined the frequency of the 5'UTR variant -77T>C (rs 3213235) in 247 French breast cancer (BC) patients, 66 of whom were adverse radiotherapy responders and 380 controls and determined the haplotypes based on this and the previously genotyped variants Arg194Trp, Arg280His and Arg399Gln. The -77T>C variant alone showed no significant association with BC risk or therapeutic radiation sensitivity. The H5 haplotype (variant allele codon 280, wildtype allele other positions) was associated with increased BC risk (OR 1.90, 95% confidence interval 1.12-3.23) and the H3 haplotype (wildtype allele all four positions) was inversely associated with therapeutic radiation sensitivity compared with the reference group (H1 haplotype, -77C, wildtype allele codons 194, 280, 399) (OR 0.39, 95% confidence interval 0.16-0.92). However given that the global tests for association were not significant these results should be interpreted carefully. Lymphoblastoid cell lines heterozygous for the H1/H3 haplotypes had a significantly higher cell survival (P=0.04) after exposure to ionising radiation (IR) than those with the H1/H1 haplotypes, in agreement with the association study. However no haplotype-specific differences in XRCC1 expression or cell cycle progression were noted in the 24 hours following IR exposure. These results suggest that the -77T>C genotype or another variant in linkage disequilibrium influences the cellular response to DNA damage, although the underlying molecular mechanisms remain to be established.
Received April 20, 2006
Revised June 1, 2006
Accepted June 20, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
The XRCC1 -77T>C variant: haplotypes, breast cancer risk, response to radiotherapy and the cellular response to DNA damage
Reto Brem 1,
David G. Cox 2,
Brigitte Chapot 1,
Norman Moullan 1,
Pascale Romestaing 3,
Jean-Pierre Gerard 4,
Paola Pisani 1,
and
Janet Hall 5 *
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA
3 Centre Hospitalier Lyon-Sud, Radiothérapie, Curiethérapie, Oncologie, 5 chemin du Grand-Revoyet, 69496, Pierre Bénite, France
4 Centre Antoine-Lacassagne, 33 avenue de Valombrose, 06189 Nice, cedex 2, France
5 International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon, France; Present address: Institut Curie, Bâts. 110-112, Centre Universitaire, 91898 Orsay cedex, France
Janet Hall, E-mail: janet.hall{at}curie.u-psud.fr
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