Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Sci Rep. 2021 Nov 2;11(1):21520. doi: 10.1038/s41598-021-00909-z.
We investigated the association between genetic variants in the histone modification regions and the prognosis of lung adenocarcinoma after curative surgery. Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The SNPs were analyzed in a discovery set (n = 166) and a validation set (n = 238). The associations of the SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. A total of 279 SNPs were selected for genotyping. Among these, CAPN1 rs17583C>T was significantly associated with better OS and DFS (P = 0.001 and P = 0.007, respectively), and LINC00959 rs4751162A>G was significantly associated with worse DFS (P = 0.008). Luciferase assays showed a significantly lower promoter activity of CAPN1 in the rs17583 T allele than C allele (P = 0.008), and consistently the CT + TT genotypes had significantly lower CAPN1 expression than CC genotype (P = 0.01) in clinical samples. The rs4751162 G allele had higher promoter activity of GLRX3 than A allele (P = 0.05). The motif analyses and ChIP-qPCR confirmed that the variants are located in the active promoter/enhancer regions where transcription factor binding occurs. This study showed that genetic variants in the histone modification regions could predict the prognosis of lung adenocarcinoma after surgery.
我们研究了组蛋白修饰区域的遗传变异与根治性手术后肺腺癌预后的关系。使用 ChIP-seq 和 RNA-seq 的综合分析选择潜在的功能 SNP。在发现集（n=166）和验证集（n=238）中分析了 SNP。分析了 SNP 与总生存期（OS）和无病生存期（DFS）的相关性。总共选择了 279 个 SNP 进行基因分型。其中，CAPN1 rs17583C>T 与更好的 OS 和 DFS 显著相关（P=0.001 和 P=0.007），LINC00959 rs4751162A>G 与更差的 DFS 显著相关（P=0.008）。荧光素酶检测显示，rs17583 T 等位基因的 CAPN1 启动子活性明显低于 C 等位基因（P=0.008），在临床样本中，CT+TT 基因型的 CAPN1 表达明显低于 CC 基因型（P=0.01）。rs4751162 G 等位基因的 GLRX3 启动子活性高于 A 等位基因（P=0.05）。 motif 分析和 ChIP-qPCR 证实了这些变体位于转录因子结合发生的活性启动子/增强子区域。本研究表明，组蛋白修饰区域的遗传变异可预测手术后肺腺癌的预后。
