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Variants in DNA double-strand break repair and DNA damage-response genes and susceptibility to lung and head and neck cancers

Danoy, Patrick
Michiels, Stefan
Dessen, Philippe
Pignat, Cécile
Boulet, Thomas
Monet, Marion
Lathrop, Mark
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Published in International Journal of Cancer. 2008, vol. 123, no. 2, p. 457-63
Abstract 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.
Keywords AdultAgedCase-Control StudiesConfounding Factors (Epidemiology)DNA Breaks, Double-StrandedDNA DamageDNA RepairFemaleFrance/epidemiologyGene DeletionGene FrequencyGenetic Predisposition to DiseaseGenotypeHaplotypesHead and Neck Neoplasms/epidemiology/geneticsHumansLung Neoplasms/epidemiology/geneticsMaleMiddle AgedMutagenesis, InsertionalPolymorphism, GeneticPolymorphism, Single NucleotideRad52 DNA Repair and Recombination Protein/geneticsRecQ Helicases/geneticsResearch DesignRisk AssessmentRisk FactorsSmoking/adverse effects
PMID: 18449888
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Research group Groupe Bouchardy Magnin Christine (Registre genevois des tumeurs) (532)
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DANOY, Patrick et al. Variants in DNA double-strand break repair and DNA damage-response genes and susceptibility to lung and head and neck cancers. In: International Journal of Cancer, 2008, vol. 123, n° 2, p. 457-63. https://archive-ouverte.unige.ch/unige:1720

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Deposited on : 2009-05-26

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