Seo Hyewon, Jung Deuk Kju, Kang Hyo-Gyoung, Jeong Ji Yun, Lee Shin Yup, Choi Jin Eun, Hong Mi Jeong, Do Sook Kyung, Lee Jang Hyuck, Lee Won Kee, Shin Kyung Min, Yoo Seung Soo, Lee Jaehee, Cha Seung Ick, Kim Chang Ho, Park Jae Yong
Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Department of Biochemistry and Cell Biology, 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.
Cancer Genet. 2018 Dec;228-229:73-82. doi: 10.1016/j.cancergen.2018.10.002. Epub 2018 Oct 16.
We conducted this study to identify regulatory variants in cancer-related pathway genes which can predict clinical outcomes of chemotherapy in advanced NSCLC, using a comprehensive list of regulatory SNPs prioritized by RegulomeDB.
A total of 509 potentially functional SNPs in cancer-related pathway genes were evaluated. The SNPs were analyzed in a discovery set (n = 198), and an independent validation set (n = 181). The associations of the SNPs with chemotherapy response and overall survival (OS) were analyzed.
In the discovery set, 95 SNPs were significantly associated with clinical outcomes. Among the 95 SNPs, only rs10414193A > G in the intronic region of ARID3A, an eQTL for LKB1, was consistently associated with chemotherapy response and OS in the validation set. In combined analysis, the rs10414193A > G was significantly associated with worse response to chemotherapy (adjusted odds ratio = 0.63, 95% CI = 0.47-0.85, P = 0.002), and with worse OS (adjusted hazard ratio = 1.25, 95% CI = 1.08-1.45, P = 0.004). Luciferase assay showed a significantly higher LKB1 promoter activity associated with rs10414193G allele compared with rs10414193A allele (P = 0.0009).
Our results suggest that rs10414193A > G may be useful for the prediction of clinical outcomes of chemotherapy in advanced NSCLC.
我们开展这项研究，旨在利用RegulomeDB优先列出的调控性单核苷酸多态性（SNP）综合清单，鉴定癌症相关通路基因中的调控性变异，这些变异可预测晚期非小细胞肺癌（NSCLC）化疗的临床结局。
共评估了癌症相关通路基因中的509个潜在功能性SNP。在一个发现集（n = 198）和一个独立验证集（n = 181）中对这些SNP进行了分析。分析了SNP与化疗反应及总生存期（OS）的关联。
在发现集中，95个SNP与临床结局显著相关。在这95个SNP中，仅位于ARID3A内含子区域的rs10414193A>G（LKB1的一个表达定量性状位点）在验证集中与化疗反应和OS始终相关。在联合分析中，rs10414193A>G与化疗反应较差显著相关（校正比值比=0.63，95%置信区间=0.47 - 0.85，P = 0.002），且与较差的OS相关（校正风险比=1.25，95%置信区间=1.08 - 1.45，P = 0.004）。荧光素酶检测显示，与rs10414193A等位基因相比，rs10414193G等位基因的LKB1启动子活性显著更高（P = 0.0009）。
我们的结果表明，rs10414193A>G可能有助于预测晚期NSCLC化疗的临床结局。
