Variants in DNA double-strand break repair and DNA damage-response genes and susceptibility to lung and head and neck cancers.
Cigarette smoking is the major risk factor for lung cancer, and together with alcohol for head and neck (H--N) cancer. These genotoxics produced DNA damage and particularly double-strand breaks (DSB) that are removed by various repair pathways. To understand the initiation of these cancers, we performed a genotype analysis to correlate some variants in specific genes in a case-control study of lung and H-N cancers. In a discovery phase, we sequenced DNA samples of 32 healthy Caucasians to describe genetic variants in 30 genes involved in the repair of DSB and in DNA damage response. 625 variants were detected on 29 out of the 30 genes successfully screened by sequencing exons, parts of introns and flanking regions. These included 470 non-exonic variants, from which 33 insertions/deletions, and 155 exonic alterations, corresponding to 59 non synonymous polymorphisms. 223 of these variants were not previously described. In total, 379 variants were successfully genotyped in a case-control study restricted to smokers including 151 lung cases, 251 H-N cases, and 172 controls. To account for multiple testing, we associated to each p-value a proportion of false positives (q-value). Haplotype-analysis suggested potential associations (p < 0.05) between lung cancer and 2 genes (RECQL4 and RAD52), which came with q-value of 8%, and between H-N cancer and 1 gene (DNA-PK) but with q-value of 56%. The 3 genes are key players for regulating the efficiency of DSB repair. Large-scale studies are needed to show if any of these 3 variants are truly associated with an increased risk of cancer.
Danoy
Patrick
P
Centre National de Génotypage, Evry, France.
Michiels
Stefan
S
Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, France.|INSERM, U794, Centre d'Etude du Polymorphisme Humain, Paris, France.
Dessen
Philippe
P
CNRS, FRE2939, Université Paris-Sud, Institut Gustave Roussy, Villejuif, France.
Pignat
Cécile
C
Centre National de Génotypage, Evry, France.
Boulet
Thomas
T
Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, France.
Monet
Marion
M
Centre National de Génotypage, Evry, France.
Bouchardy
Christine
C
Geneva Cancer Registry, Switzerland.
Lathrop
Mark
M
Centre National de Génotypage, Evry, France.
Sarasin
Alain
A
CNRS, FRE2939, Université Paris-Sud, Institut Gustave Roussy, Villejuif, France.
Benhamou
Simone
S
INSERM, U794, Centre d'Etude du Polymorphisme Humain, Paris, France.|CNRS, FRE2939, Université Paris-Sud, Institut Gustave Roussy, Villejuif, France.
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015986:Confounding Factors, Epidemiologic; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D005602:France / Q000453:epidemiology; D017353:Gene Deletion; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006258:Head and Neck Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics; D053484:RecQ Helicases / Q000235:genetics; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects
C497194:RAD52 protein, human; D051721:Rad52 DNA Repair and Recombination Protein; C506731:RECQL4 protein, human; D053484:RecQ Helicases