Polymorphism discovery in 62 DNA repair genes and haplotype associations with risks for lung and head and neck cancers
Polymorphism discovery in 62 DNA repair genes and haplotype associations with risks for lung and head and neck cancers
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DOI：
10.1093/carcin/bgm111
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发表时间：
2007-08-01
期刊：
影响因子：
4.7
通讯作者：
Benhamou, Simone
中科院分区：
文献类型：
--
作者：
Michiels, Stefan;Danoy, Patrick;Benhamou, Simone
DNA修复对于维持遗传稳定性至关重要。我们进行了测序，以确定70个基因中的常见遗传变异，这些基因涉及三个主要的修复途径（碱基切除修复，核苷酸切除修复和错配修复）和DNA合成，并研究了它们与肺癌和头颈癌（HN）的关系。在检测的70个基因中，通过对来自健康高加索个体的32个DNA样品中的外显子、部分内含子和侧翼区进行测序，成功地筛选了62个基因（外显子覆盖率> 20%）。所使用的策略允许在测序的区域中检测几乎所有次要等位基因频率>= 5%的变体。在单核苷酸多态性（SNP）发现期间，在内含子或基因侧翼区域中检测到772个序列，在单核苷酸多态性（SNP）发现期间在外显子中发现313个序列（导致113个非同义变异）。总共在151例肺癌病例、251例H-N癌症病例和172例医院对照中成功地对695种变异进行了基因分型。在非条件logistic回归模型中，使用评分统计来检验病例和对照之间单倍型频率的差异。为了解释多重检验，我们将每个P值与错误发现的估计比例相关联。单倍型分析显示，肺癌与8个基因（MSH 3、MLH 3、POLK、LIG 1、ERCC 5、PMS 1、POLG 2和RPA 3）之间以及H-N癌与4个基因（PMS 1、POLG 2、POLR 2B和RPA 1）之间存在潜在关联（P < 0.05），错误发现率分别为25%和55%。DNA合成途径显示H-N病例和对照组之间SNP等位基因频率的差异比随机预期的要大（P = 0.05）。这些结果暗示了一些潜在的候选人，可在更大的研究中进行进一步调查。
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, micleotide 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.