TY - JOUR
T1 - Polymorphism discovery in 62 DNA repair genes and haplotype associations with risks for lung and head and neck cancers
AU - Michiels, Stefan
AU - Danoy, Patrick
AU - Dessen, Philippe
AU - Bera, Alex
AU - Boulet, Thomas
AU - Bouchardy, Christine
AU - Lathrop, Mark
AU - Sarasin, Alain
AU - Benhamou, Simone
PY - 2007/8/1
Y1 - 2007/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34548103488&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgm111
DO - 10.1093/carcin/bgm111
M3 - Article
C2 - 17494052
AN - SCOPUS:34548103488
SN - 0143-3334
VL - 28
SP - 1731
EP - 1739
JO - Carcinogenesis
JF - Carcinogenesis
IS - 8
ER -