Medical Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Clin Breast Cancer. 2019 Feb;19(1):e220-e238. doi: 10.1016/j.clbc.2018.09.004. Epub 2018 Sep 19.
Genetic susceptibility for breast cancer (BC) is still poorly understood. A combination of multiple low-penetrant alleles of cancer-related genes and gene-gene interactions (epistasis) contributes to BC risk. Genetic variants in receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), chitinase-3-like protein 1 (CHI3L1), and vitamin D receptor (VDR) genes are implicated in breast carcinogenesis; however, the influence of their epistatic effects on BC susceptibility has not yet been studied. We investigated the association of single nucleotide polymorphism (SNP)-SNP interactions and haplotypes of 6 SNPs in these 4 genes with the genetic predisposition of BC in Egyptian women.
Data of 115 BC patients and 120 cancer-free controls were studied. Association tests were conducted using logistic regression models.
Individual SNPs showed weak statistical significance with BC susceptibility. The interactions between RANKL-rs9533156 and OPG-rs2073618; OPG-rs2073618 with CHI3L1-rs4950928, VDR-rs2228570 and VDR-rs1544410; OPG-rs2073617 and VDR-rs1544410; VDR-rs2228570 and VDR-rs1544410 were strongly associated with increased BC risk after adjustment for multiple comparisons. No SNPs were in strong linkage disequilibrium. The TCTCTG-rs9533156-rs2073618-rs2073617-rs4950928-rs2228570-rs1544410 haplotype was significantly associated with increased BC risk (adjusted odds ratio = 8.33; 95% confidence interval, 1.32-52.46; P = .025) compared with controls. TCCCTG haplotype stratified BC patients according to estrogen receptor/progesterone receptor status. TCTCTA was positively associated, and TCTCTG and TGTCTG haplotypes inversely correlated with bone metastasis. Bioinformatic analysis revealed 13 proteins commonly interacting with our 4 genes; the most significant was signal transducer and activator of transcription 5B.
Our results suggested that a stronger combined effect of SNPs in RANKL, OPG, CHI3L1, and VDR genes via gene-gene interaction may help predict BC risk and prognosis.
乳腺癌（BC）的遗传易感性仍知之甚少。癌症相关基因的多个低外显率等位基因和基因-基因相互作用（上位性）的组合导致了 BC 的风险。核因子κB 配体（RANKL）、骨保护素（OPG）、几丁质酶 3 样蛋白 1（CHI3L1）和维生素 D 受体（VDR）基因中的遗传变异与乳腺癌的发生有关；然而，其上位性效应对 BC 易感性的影响尚未得到研究。我们研究了这些 4 个基因中的 6 个单核苷酸多态性（SNP）-SNP 相互作用和单倍型与埃及女性乳腺癌遗传易感性的关系。
研究了 115 例 BC 患者和 120 例无癌症对照者的数据。使用逻辑回归模型进行关联检验。
单个 SNP 与 BC 易感性呈弱统计学意义。RANKL-rs9533156 和 OPG-rs2073618 之间的相互作用；OPG-rs2073618 与 CHI3L1-rs4950928、VDR-rs2228570 和 VDR-rs1544410 之间；OPG-rs2073617 和 VDR-rs1544410；VDR-rs2228570 和 VDR-rs1544410 在经过多次比较调整后与 BC 风险增加强烈相关。没有 SNP 处于强连锁不平衡状态。TCTCTG-rs9533156-rs2073618-rs2073617-rs4950928-rs2228570-rs1544410 单倍型与 BC 风险增加显著相关（调整后的优势比=8.33；95%置信区间，1.32-52.46；P=0.025）与对照组相比。TCCCTG 单倍型根据雌激素受体/孕激素受体状态对 BC 患者进行分层。TCTCTA 呈正相关，而 TCTCTG 和 TGTCTG 单倍型与骨转移呈负相关。生物信息学分析显示，有 13 种常见的蛋白质与我们的 4 个基因相互作用；最显著的是信号转导和转录激活因子 5B。
我们的结果表明，RANKL、OPG、CHI3L1 和 VDR 基因中 SNP 的更强组合效应通过基因-基因相互作用可能有助于预测 BC 的风险和预后。
