Genome Institute of Singapore, Human Genetics, Singapore, Singapore.
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
Breast Cancer Res Treat. 2021 Aug;188(3):713-727. doi: 10.1007/s10549-021-06185-9. Epub 2021 Mar 26.
A breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic variation, regulation, and expression to clarify the molecular alterations associated with these variants.
Genome-wide methylomic variation was quantified (MethylationEPIC) in Asian breast cancer patients (1152 buffy coats from peripheral whole blood). DNA methylation (DNAm) quantitative trait loci (mQTL) mapping was performed for 235 of the 313 variants with minor allele frequencies > 5%. Stability of identified mQTLs (p < 5e-8) across lifetime was examined using a public mQTL database. Identified mQTLs were also mapped to expression quantitative trait loci (eQTLs) in the Genotype-Tissue Expression Project and the eQTLGen Consortium.
Breast cancer PRS was not associated with DNAm. A higher proportion of significant cis-mQTLs were observed. Of 822 significant cis-mQTLs (179 unique variants) identified in our dataset, 141 (59 unique variants) were significant (p < 5e-8) in a public mQTL database. Eighty-six percent (121/141) of the matched mQTLs were consistent at multiple time points (birth, childhood, adolescence, pregnancy, middle age, post-diagnosis, or treatment). Ninety-three variants associated with DNAm were also cis-eQTLs (35 variants not genome-wide significant). Multiple loci in the breast cancer PRS are associated with DNAm, contributing to the polygenic nature of the disease. These mQTLs are mostly stable over time.
Consistent results from DNAm and expression data may reveal new candidate genes not previously associated with breast cancer.
包含 313 个常见变异的乳腺癌多基因风险评分（PRS）可靠地预测疾病风险。我们研究了遗传变异、调控和表达之间的可能关系，以阐明与这些变异相关的分子变化。
在亚洲乳腺癌患者（1152 份外周全血的 buffy 涂层）中定量检测了全基因组甲基化变异（MethylationEPIC）。对 313 个具有 > 5%次要等位基因频率的变体中的 235 个进行了 DNA 甲基化（DNAm）数量性状基因座（mQTL）作图。使用公共 mQTL 数据库检查鉴定的 mQTLs（p < 5e-8）在整个生命周期中的稳定性。将鉴定的 mQTLs 也映射到基因型组织表达项目和 eQTLGen 联盟中的表达数量性状基因座（eQTLs）。
乳腺癌 PRS 与 DNAm 无关。观察到更多比例的显著顺式-mQTLs。在我们的数据集，822 个显著的顺式-mQTLs（179 个独特变体）中，有 141 个（59 个独特变体）在公共 mQTL 数据库中具有统计学意义（p < 5e-8）。86%（121/141）的匹配 mQTL 在多个时间点（出生、儿童期、青春期、妊娠、中年、诊断后或治疗期间）一致。与 DNAm 相关的 93 个变体也是顺式-eQTLs（35 个变体不是全基因组显著）。乳腺癌 PRS 中的多个位点与 DNAm 相关，这是该疾病多基因性质的原因。这些 mQTL 随时间基本稳定。
来自 DNAm 和表达数据的一致结果可能揭示以前与乳腺癌无关的新候选基因。
