Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, 17177 Stockholm, Sweden.
Breast Cancer Res Treat. 2011 Apr;126(3):717-27. doi: 10.1007/s10549-010-1172-9. Epub 2010 Sep 26.
In an attempt to identify common disease susceptibility alleles for breast cancer, we performed a combined analysis of three genome-wide association studies (GWAS), involving 2,702 women of European ancestry with invasive breast cancer and 5,726 controls. Tests for association were performed for 285,984 SNPs. Evidence for association with SNPs in genes in specific pathways was assessed using a permutation-based approach. We confirmed associations with loci reported by previous GWAS on 1p11.2, 2q35, 3p, 5p12, 8q24, 10q23.13, 14q24.1 and 16q. Six SNPs with the strongest signals of association with breast cancer, and which have not been reported previously, were typed in two further studies; however, none of the associations could be confirmed. Suggestive evidence for an excess of associations was found for genes involved in the regulation of actin cytoskeleton, glycan degradation, alpha-linolenic acid metabolism, circadian rhythm, hematopoietic cell lineage and drug metabolism. Androgen and oestrogen metabolism, a pathway previously found to be associated with the development of postmenopausal breast cancer, was marginally significant (P = 0.051 [unadjusted]). These results suggest that further analysis of SNPs in these pathways may identify associations that would be difficult to detect through agnostic single SNP analyses. More effort focused in these aspects of oncology can potentially open up promising avenues for the understanding of breast cancer and its prevention.
为了鉴定乳腺癌的常见疾病易感性等位基因，我们对三项全基因组关联研究（GWAS）进行了联合分析，共纳入 2702 名欧洲裔侵袭性乳腺癌女性患者和 5726 名对照者。对 285984 个 SNP 进行了关联检验。使用基于置换的方法评估了特定通路基因中 SNP 与疾病关联的证据。我们对先前 GWAS 报道的 1p11.2、2q35、3p、5p12、8q24、10q23.13、14q24.1 和 16q 上的基因座与 SNP 的关联进行了确认。在另外两项研究中，对与乳腺癌关联最强且以前未报道过的 6 个 SNP 进行了分型；然而，这些关联均无法得到确认。在调节肌动蛋白细胞骨架、聚糖降解、α-亚麻酸代谢、昼夜节律、造血细胞谱系和药物代谢等基因中发现了过多关联的提示性证据。先前发现与绝经后乳腺癌发生相关的雄激素和雌激素代谢途径也具有显著意义（未校正 P = 0.051）。这些结果表明，对这些通路中 SNP 的进一步分析可能会发现难以通过非靶向性单 SNP 分析检测到的关联。在肿瘤学的这些方面进行更多的研究，有可能为理解乳腺癌及其预防开辟有前景的途径。
