Wang Yanru, Freedman Jennifer A, Liu Hongliang, Moorman Patricia G, Hyslop Terry, George Daniel J, Lee Norman H, Patierno Steven R, Wei Qingyi
Duke Cancer Institute, Duke University Medical Center, Durham, NC.
Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC.
Int J Cancer. 2017 Aug 15;141(4):731-743. doi: 10.1002/ijc.30787. Epub 2017 Jun 1.
Evidence suggests that cells with a stemness phenotype play a pivotal role in oncogenesis, and prostate cells exhibiting this phenotype have been identified. We used two genome-wide association study (GWAS) datasets of African descendants, from the Multiethnic/Minority Cohort Study of Diet and Cancer (MEC) and the Ghana Prostate Study, and two GWAS datasets of non-Hispanic whites, from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the Breast and Prostate Cancer Cohort Consortium (BPC3), to analyze the associations between genetic variants of stemness-related genes and racial disparities in susceptibility to prostate cancer. We evaluated associations of single-nucleotide polymorphisms (SNPs) in 25 stemness-related genes with prostate cancer risk in 1,609 cases and 2,550 controls of non-Hispanic whites (4,934 SNPs) and 1,144 cases and 1,116 controls of African descendants (5,448 SNPs) with correction by false discovery rate ≤0.2. We identified 32 SNPs in five genes (TP63, ALDH1A1, WNT1, MET and EGFR) that were significantly associated with prostate cancer risk, of which six SNPs in three genes (TP63, ALDH1A1 and WNT1) and eight EGFR SNPs showed heterogeneity in susceptibility between these two racial groups. In addition, 13 SNPs in MET and one in ALDH1A1 were found only in African descendants. The in silico bioinformatics analyses revealed that EGFR rs2072454 and SNPs in linkage with the identified SNPs in MET and ALDH1A1 (r > 0.6) were predicted to regulate RNA splicing. These variants may serve as novel biomarkers for racial disparities in prostate cancer risk.
有证据表明，具有干性表型的细胞在肿瘤发生中起关键作用，并且已经鉴定出表现出这种表型的前列腺细胞。我们使用了来自饮食与癌症多族裔/少数族裔队列研究（MEC）和加纳前列腺研究的两个非洲后裔全基因组关联研究（GWAS）数据集，以及来自前列腺、肺、结肠直肠和卵巢（PLCO）癌症筛查试验和乳腺癌与前列腺癌队列联盟（BPC3）的两个非西班牙裔白人GWAS数据集，来分析干性相关基因的遗传变异与前列腺癌易感性种族差异之间的关联。我们评估了25个干性相关基因中的单核苷酸多态性（SNP）与1609例非西班牙裔白人病例和2550例对照（4934个SNP）以及1144例非洲后裔病例和1116例对照（5448个SNP）的前列腺癌风险的关联，并通过错误发现率≤0.2进行校正。我们在五个基因（TP63、ALDH1A1、WNT1、MET和EGFR）中鉴定出32个与前列腺癌风险显著相关的SNP，其中三个基因（TP63、ALDH1A1和WNT1）中的六个SNP以及八个EGFR SNP在这两个种族群体之间的易感性存在异质性。此外，仅在非洲后裔中发现了MET中的13个SNP和ALDH1A1中的一个SNP。计算机生物信息学分析表明，EGFR rs2072454以及与MET和ALDH1A1中鉴定出的SNP连锁的SNP（r>0.6）被预测可调节RNA剪接。这些变异可能作为前列腺癌风险种族差异的新型生物标志物。
