Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, Chicago, Illinois.
Mol Carcinog. 2018 Oct;57(10):1311-1318. doi: 10.1002/mc.22845. Epub 2018 Jun 14.
Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (P = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, P = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.
在乳腺癌中，Hippo 通路中的基因表达变化与肿瘤体积大及转移相关。该通路中基因的遗传变异的联合效应可能在乳腺癌的发生中起因果作用。我们利用 Root 联盟的乳腺癌全基因组关联研究的数据，对 35 个 Hippo 通路基因中的 7086 个 SNP 进行了检测，这些 SNP 之间的相关性（r<0.8）不高。Root 联盟的数据来自于来自尼日利亚、美国和巴巴多斯的 3686 名非洲裔参与者：1657 例病例（403 例雌激素受体阳性[ER+]，374 例 ER-）和 2029 例对照。使用改良的 AdaJoint 检验对大型遗传关联研究进行基因水平分析，调整了年龄、研究地点和主成分分析的前四个特征向量。SNP 水平的分析使用逻辑回归进行。Hippo 通路与 ER+乳腺癌的风险显著相关（通路水平 P=0.019），其中 WWC1（P=0.04）是主要基因。在没有 WWC1 的情况下，通路水平的显著性丧失（P=0.12）。在基因水平调整了多重比较后，WWC1 基因中的 rs147106204 是最具统计学意义的 SNP（OR=0.53，95%CI=0.41-0.70，P=0.025）。我们发现 Hippo 通路中的遗传变异与 ER+乳腺癌之间存在关联。此外，WWC1 被确定为最重要的遗传易感性位点，突出了在研究较少的人群中进行乳腺癌遗传流行病学研究的重要性。
