The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Division of Molecular Pathology, Amsterdam, The Netherlands.
University of Cambridge, Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK.
Br J Cancer. 2019 Mar;120(6):647-657. doi: 10.1038/s41416-019-0393-x. Epub 2019 Feb 21.
We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.
Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).
We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.
We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
我们通过对欧洲裔女性的大型荟萃分析，研究了种系变异与乳腺癌死亡率之间的关联。
荟萃分析包括基于 Cox 模型的 12 个数据集的汇总估计，这些数据集共纳入了 96661 名患有乳腺癌和 7697 例（乳腺癌特异性死亡）事件的女性的约 1040 万个变体。雌激素受体（ER）特异性分析基于 64171 例 ER 阳性（4116 例）和 16172 例 ER 阴性（2125 例）患者。我们使用贝叶斯假发现概率（BFDP）评估信号为真阳性的概率。
我们没有发现任何与乳腺癌特异性死亡率相关的 P < 5 × 10 的变体。对于 ER 阳性疾病，最显著相关的变体是 chr7:rs4717568（BFDP = 7%，P = 1.28 × 10 ，危险比 [HR] = 0.88，95%置信区间 [CI] = 0.84-0.92）；最接近的基因是 AUTS2。对于 ER 阴性疾病，最显著的变体是 chr7:rs67918676（BFDP = 11%，P = 1.38 × 10 ，HR = 1.27，95%CI = 1.16-1.39）；位于长非编码 RNA 基因（AC004009.3）内，靠近 HOXA 基因簇。
我们发现了染色体 7 上的种系变异，BFDP < 15%，这些变异接近与乳腺癌结局有生物学证据相关的基因。然而，在全基因组显著水平与死亡率相关的变异很少，这突显了为乳腺癌患者提供基于遗传的个体化预后信息所面临的挑战。
