Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
Cancer Epidemiol Biomarkers Prev. 2012 Jul;21(7):1097-104. doi: 10.1158/1055-9965.EPI-11-1123-T. Epub 2012 Apr 26.
Genome-wide association studies have identified two independent lung cancer susceptibility loci at chromosome 15q25 and one locus at 5p15. We examined the association of genetic variants in these regions with gene expression in lung tumor tissue, in an effort to elucidate carcinogenic mechanisms by which these variants influence lung cancer risk.
We used data from 2 independent studies of non-small cell lung carcinoma patients: the JBR.10 clinical trial (n = 131) and a University Health Network (UHN) patient sample in Toronto (n = 181). We genotyped seven 15q25 and five 5p15 variants and examined their association with expression profiles of genes in the corresponding regions, measured by Affymetrix HG-U133A.
The minor allele (C) of a variant representing one of the two loci at 15q25 (rs2036534) was associated with increased iron-responsive element binding protein 2 (IREB2) expression in both studies (JBR.10 P = 0.042; UHN P = 0.002). A false discovery rate of 0.05 or less in the UHN sample increased our confidence in this association. The association appears to be more prominent among lung adenocarcinoma patients. We did not detect an association between genotype and expression profile for the other 15q25 locus or for 5p15 variants.
In contrast to previous studies that indicate 15q25 variants are associated with lung cancer risk through an effect on smoking behavior, our results suggest these variants may influence risk through a second mechanism, involving modulation of IREB2 expression.
This finding expands on potential mechanisms through which 15q25 variants influence lung cancer risk and may have implications for future research on chemoprevention strategies.
全基因组关联研究已经确定了两个位于染色体 15q25 的独立肺癌易感性位点和一个位于 5p15 的位点。我们研究了这些区域中遗传变异与肺癌肿瘤组织中基因表达的关联，旨在阐明这些变异影响肺癌风险的致癌机制。
我们使用了来自两个非小细胞肺癌患者的独立研究的数据：JBR.10 临床试验（n=131）和多伦多大学健康网络（UHN）患者样本（n=181）。我们对七个 15q25 和五个 5p15 变体进行了基因分型，并通过 Affymetrix HG-U133A 检测了它们与相应区域基因表达谱的关联。
15q25 上两个位点之一的一个变体（rs2036534）的次要等位基因（C）与两个研究中的铁反应元件结合蛋白 2（IREB2）表达增加相关（JBR.10 P=0.042；UHN P=0.002）。在 UHN 样本中，假发现率（FDR）小于或等于 0.05 增加了我们对这种关联的信心。这种关联似乎在肺腺癌患者中更为明显。我们没有检测到其他 15q25 位点或 5p15 变体的基因型与表达谱之间的关联。
与之前表明 15q25 变体通过对吸烟行为的影响与肺癌风险相关的研究不同，我们的结果表明这些变体可能通过影响 IREB2 表达的第二种机制来影响风险。
这一发现扩展了 15q25 变体影响肺癌风险的潜在机制，并可能对未来的化学预防策略研究产生影响。
