Carcinogenesis Advance Access published online on May 10, 2007
Carcinogenesis, doi:10.1093/carcin/bgm111
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Polymorphism discovery in 62 DNA repair genes and haplotype-associations with risks for lung, and head and neck cancers
1 Institut Gustave Roussy, Department of Biostatistics and Epidemiology, Villejuif, France
2 INSERM, U794, Evry, France
3 Université d'Evry, UMR-S794, Evry, France
4 Centre National de Génotypage, Evry, France
5 Université Paris-Sud, CNRS, FRE2939, Institut Gustave Roussy, Villejuif, France
6 Geneva Cancer Registry, Switzerland
Correspondence and requests for reprints should be addressed to: Dr Simone BENHAMOU, CNRS FRE2939, Institut Gustave Roussy, Espace Maurice Tubiana, 39 rue Camille Desmoulins, 94805 Villejuif cedex, FRANCE, Phone: (+33) 1 42114139, Fax: (+33) 1 42115315, Email: simone.benhamou{at}igr.fr
DNA repair is essential for the maintenance of genetic stability. We undertook sequencing to determine common genetic variants in 70 genes involved in 3 major repair pathways (BER, NER, MMR) and in DNA synthesis, and investigated their relationship to lung and head and neck (H-N) cancers.
Of the 70 genes examined, 62 were successfully screened (exon coverage > 20%) by sequencing exons, parts of introns and flanking regions in 32 DNA samples from healthy Caucasian individuals. The strategy used allowed the detection of almost all variants with a minor allele frequency 
5% in the regions sequenced. 772 sequence variations were detected in introns or regions flanking the gene, and 313 were found in exons (leading to 113 non-synonymous variations) during SNP discovery. 695 variants were successfully genotyped in 151 lung cancer cases, 251 H-N cancer cases, and 172 hospital controls. Score statistics were used to test differences in haplotype frequencies between cases and controls in an unconditional logistic regression model. To account for multiple testing, we associated to each p-value the expected proportion of false discoveries.
Haplotype-analysis revealed potential associations (p<0.05) between lung cancer and 8 genes (MSH3, MLH3, POLK, LIG1, ERCC5, PMS1, POLG2 and RPA3), and between H-N cancer and 4 genes (PMS1, POLG2, POLR2B and RPA1) with false discovery proportions of 25% and 55%, respectively. The DNA synthesis pathway showed a tendency for more differential SNP allele frequencies between H-N cases and controls than expected by chance (p=0.05). These results hint to a few potential candidates for further investigation in larger studies.
Key Words: DNA repair • gene polymorphisms • association study • lung cancer • head and neck cancer
* These authors contributed equally to this work
Received February 12, 2007; revised April 5, 2007; accepted April 30, 2007.