Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland and Labrador, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
PLoS One. 2018 Jun 12;13(6):e0198873. doi: 10.1371/journal.pone.0198873. eCollection 2018.
The Brahma gene (BRM) encodes a catalytic ATPase subunit of the Switch/Sucrose non-fermentable (SWI/SNF) complex, which modulates gene expression and many important cellular processes. Two indel polymorphisms in the promoter region of BRM (BRM-741 and BRM-1321) are associated with its reduced expression and the risk of susceptibility or survival outcomes in multiple solid cancers. In this study, we have examined these variants in relation to susceptibility and survival outcomes in colorectal cancer.
Genotypes were obtained using TaqMan assays in 427 cases and 408 controls. Multivariate logistic and Cox regression models were fitted to examine the associations of the BRM-741 and BRM-1321 genotypes adjusting for relevant covariates. Sub-group analyses based on tumor location and patient sex were also performed. In all analyses, indels were examined individually as well as in combination.
Our results showed that there was no association between the BRM polymorphisms and the risk of colorectal cancer. However, genotype combinations of the BRM-741 and BRM-1321 variants were associated with the risk of colon cancer. Particularly, patients having at least one variant allele had increased risk of colon cancer when compared to patients with the double wild-type genotype. In the survival analyses, BRM-741 heterozygosity was associated with longer progression-free survival time in the colorectal cancer patients. A stronger association was detected in the male patients under the recessive genetic model where the homozygosity for the variant allele of BRM-741 was associated with shorter progression-free survival time.
Our analyses suggest that BRM-741 and BRM-1321 indels are associated with the risk of developing colon cancer and the BRM-741 indel is associated with the disease progression in colorectal cancer patients, especially in the male patients. Although our results show a different relationship between these indels and colorectal cancer compared to other cancer sites, they also suggest that BRM and its promoter variants may have biological roles in susceptibility and survival outcomes in colorectal cancers. Performing further analyses in additional and larger cohorts are needed to confirm our conclusions.
Brahma 基因（BRM）编码 Switch/Sucrose non-fermentable（SWI/SNF）复合物的催化 ATP 酶亚基，调节基因表达和许多重要的细胞过程。BRM 启动子区域的两个插入/缺失多态性（BRM-741 和 BRM-1321）与表达降低以及多种实体癌的易感性或生存结局风险相关。本研究检测了这些变体与结直肠癌易感性和生存结局的关系。
使用 TaqMan 分析在 427 例病例和 408 例对照中获得基因型。使用多变量逻辑和 Cox 回归模型，在调整相关协变量后，检验 BRM-741 和 BRM-1321 基因型与易感性和生存结局的关系。还基于肿瘤位置和患者性别进行了亚组分析。在所有分析中，分别和组合检测插入缺失。
我们的结果表明，BRM 多态性与结直肠癌风险之间没有关联。然而，BRM-741 和 BRM-1321 变体的基因型组合与结肠癌风险相关。特别是，与具有双野生型基因型的患者相比，至少有一种变异等位基因的患者患结肠癌的风险增加。在生存分析中，BRM-741 杂合性与结直肠癌患者的无进展生存期延长相关。在隐性遗传模型下，BRM-741 变体的纯合性与无进展生存期缩短相关，在男性患者中检测到更强的关联。
我们的分析表明，BRM-741 和 BRM-1321 插入缺失与结肠癌的发病风险相关，BRM-741 插入缺失与结直肠癌患者的疾病进展相关，特别是在男性患者中。尽管我们的结果显示这些插入缺失与结直肠癌之间的关系与其他癌症部位不同，但它们也表明 BRM 及其启动子变体可能在结直肠癌的易感性和生存结局中具有生物学作用。需要在更大的队列中进行进一步分析以证实我们的结论。
