International Agency for Research on Cancer, Lyon 69008, France.
Carcinogenesis. 2010 Apr;31(4):625-33. doi: 10.1093/carcin/bgq001. Epub 2010 Jan 27.
Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3).
Genotype data from 15 ILCCO case-control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk.
Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 x 10(-4)). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11,722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89-0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85-0.95), P = 1 x 10(-4)].
This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.
在个体研究中分析候选基因，仅发现少数与肺癌风险有明确关联的特定基因变异。在国际肺癌协作组（ILCCO）中，我们针对 10 个常见变异体进行了协调基因分型研究，这些变异体是根据与肺癌相关的先前证据选择的。这些变异体属于不同癌症相关途径的候选基因，包括炎症（IL1B）、叶酸代谢（MTHFR）、调节功能（AKAP9 和 CAMKK1）、细胞黏附（SEZL6）和细胞凋亡（FAS、FASL、TP53、TP53BP1 和 BAT3）。
来自 15 个 ILCCO 病例对照研究的基因型数据可用于总共 8431 例欧洲裔和亚洲裔肺癌病例和 11072 例对照。采用非条件逻辑回归模型分析每个变异体与肺癌风险之间的关联。
仅 TP53BP1（rs560191）的非同义变异与肺癌风险相关（OR=0.91，P=0.002）。这种关联在鳞状细胞癌中更为明显（OR=0.86，P=6×10(-4)）。未观察到中心、种族、吸烟状态、年龄组或性别存在异质性。为了确认这种关联，我们纳入了一组独立研究（9966 例/11722 例对照）中该变异体的结果，并报告了类似的结果。当将所有这些研究结合在一起时，我们报告了一个总体 OR=0.93（0.89-0.97）（P=0.001）。这种关联仅在鳞状细胞癌中显著[OR=0.89（0.85-0.95），P=1×10(-4)]。
这项研究表明，rs560191 与肺癌风险相关，进一步强调了联盟在复制或反驳已发表的遗传关联方面的价值。
