Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
Nat Commun. 2016 Sep 7;7:12675. doi: 10.1038/ncomms12675.
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
19p13 上的一个基因座与乳腺癌（BC）和卵巢癌（OC）风险相关。在这里，我们分析了该区域内的 438 个 SNP，这些 SNP 存在于 46451 名 BC 患者和 15438 名 OC 患者、15252 名 BRCA1 基因突变携带者和 73444 名对照者中，确定了 13 个与浆液性 OC（P=9.2×10(-20)）、ER 阴性 BC（P=1.1×10(-13)）、BRCA1 相关 BC（P=7.7×10(-16)）和三阴性 BC（P-diff=2×10(-5)）相关的候选因果 SNP。候选靶基因ANKLE1（P=2×10(-3)）和 ABHD8（P<2×10(-3)）的基因型-基因表达关联已被确定。染色体构象捕获鉴定了四个候选 SNP 与 ABHD8 之间的相互作用，荧光素酶检测表明六个风险等位基因增加了 ADHD8 启动子的转录激活。在假定的增强子中包含风险 SNP rs56069439 的区域内进行靶向缺失会导致 ANKLE1 的下调；mRNA 稳定性检测表明 ANKLE1 3'-UTR SNP 具有功能效应。总之，这些数据表明 19p13 上的多个 SNP 调节 ABHD8 并可能调节 ANKLE1 的表达，并表明乳腺癌和卵巢癌风险的共同机制。
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