Carcinogenesis Advance Access originally published online on May 10, 2007
Carcinogenesis 2007 28(8):1731-1739; 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 Department of Biostatistics and Epidemiology, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif cedex, France
2 Institut National de la Santé et de la Recherche Médicale, U794, Evry, France
3 Université d'Evry, UMR-S794, Evry, France
4 Centre National de Génotypage, 91057 Evry, France
5 Centre National de la Recherche Scientifique, FRE2939, Institut Gustave Roussy, Université Paris-Sud, 39 rue Camille Desmoulins, 94805 Villejuif cedex, France
6 Geneva Cancer Registry, 1205 Switzerland
* To whom correspondence should be addressed. Tel: +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 three major repair pathways (base excision repair, nucleotide excision repair and mismatch repair) 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. During single-nucleotide polymorphism (SNP) discovery, 772 sequences were detected in introns or regions flanking the gene and 313 were found in exons (leading to 113 non-synonymous variations) during single-nucleotide polymorphism (SNP) discovery. In total, 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 an estimated proportion of false discoveries. Haplotype analysis revealed potential associations (P < 0.05) between lung cancer and eight genes (MSH3, MLH3, POLK, LIG1, ERCC5, PMS1, POLG2 and RPA3) and between H-N cancer and four 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.
Abbreviations: BER, base excision repair; CI, confidence interval; H-N, head and neck; LD, linkage disequilibrium; MAF, minor allele frequency; MMR, mismatch repair; mtDNA, mitochondrial DNA; NER, nucleotide excision repair; OR, odds ratio; SNP, single-nucleotide polymorphism; UTR, untranslated region
These authors contributed equally to this work. Received February 12, 2007; revised April 5, 2007; accepted April 30, 2007.