Polymorphism discovery in 62 DNA repair genes and haplotype associations with risks for lung and head and neck cancers

Abstract

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 >or=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.

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

“…35 The corresponding genes POLK for cg05673882 and ALPP for cg23667432 are oncogenes that play roles in the formation of several age-related cancers, including breast, prostate, lung, and ovarian cancers. [36][37][38][39] The biologic functions of the remaining 3 loci within unassigned genome regions are not yet known, only locus cg01127300 has been disclosed as a potential epigenetic regulator of obesity, 40 one of the deficits of the frailty syndrome. 41 Interestingly, neither of the most strongly smoking-related CpG sites, cg05575921 (AHRR) or cg03636183 (F2RL3), 26 was identified to be related to the FI in the present study.…”

A polymorphism of the POLG2 gene is genetically associated with the invasiveness of urinary bladder cancer in Japanese males

“…16,17 Although the association between POLG2 polymorphisms and bladder cancer has not yet been established, its association with the risk of head and neck cancer was demonstrated in the French population. 18 There is no strong biological evidence to support the functional importance of POLG2 to the invasiveness of UBC. However, the increase of transcription level with the risk allele of rs17650301 may be a reason for the association.…”

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

“…16,20,21 Our sample size was sufficient to detect a 1.5-to 2.0-fold increased risk of cancer for relatively common alleles (prevalence: 10-30%), assuming an 80% power and a 5% significance level. Briefly, peripheral blood samples were available for 151 patients with lung cancer, 251 with HÀ ÀN cancer (including cancers of the oral cavity, larynx, and pharynx), and 172 control individuals who fulfilled the criteria described below.…”

“…16 In the present study, we extended the SNP discovery in the same population to genes governing DSB repair and DDR pathways. At the beginning of our experiments we choose 30 genes that we considered as central to the development of cancer: 16 involved in HR, 6 genes implicated in NHEJ and 8 genes involved in DNA damage response (Supporting Table SI).…”