Lee Soo Jung, Kang Byung Woog, Chae Yee Soo, Kim Hye Jin, Park Su Yeon, Park Jun Seok, Choi Gyu Seog, Jeon Hyo-Sung, Lee Won Kee, Kim Jong Gwang
Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Ann Surg Oncol. 2014 Dec;21 Suppl 4:S634-9. doi: 10.1245/s10434-014-3729-z. Epub 2014 Apr 28.
Assuming an association between cancer and metabolism, oncogene-directed metabolic reprogramming in cancer has revealed new target strategies. For example, the LKB1-AMPK-mTOR signaling pathway genes are already known to alter the cell metabolism and to play a critical role in the malignant behavior of cancer. Accordingly, based on the assumption that genetic variations in the LKB1-AMPK-mTOR signaling pathway can change the intracellular signal in terms of metabolic reprogramming, the present study analyzed 18 single nucleotide polymorphisms (SNPs) of the STK11, PRKAA1, TSC1/2, and mTOR genes and their impact on the survival of patients with colorectal cancer.
Seven hundred seventy-two patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. Eighteen SNPs were selected from an in silico analysis based on previous evidence of association. The SNP genotyping was performed using a SEQUENOM MassARRAY.
Among the 18 polymorphisms, three SNPs (STK11 rs741765, PRKAA1 rs461404, and TSC1 rs13295634) were significantly associated with disease-free survival (DFS) or overall survival (OS). In a multivariate analysis, the GG genotype of STK11, TT genotype of PRKAA1, and TG or GG genotype of TSC1 were identified as independent prognostic factors for a worse DFS (hazard ratio = 1.398, 1.408, and 1.388; p = 0.030, 0.013, and 0.002, respectively) and OS (hazard ratio = 1.431, 1.680, and 1.394; p = 0.038, 0.001, and 0.009, respectively).
The present results suggest that genetic variants of the STK11, PRKAA1, and TSC1 genes could be used as prognostic biomarkers for patients with surgically resected colorectal cancer.
假设癌症与代谢之间存在关联，癌症中癌基因导向的代谢重编程已揭示出新的靶向策略。例如，已知LKB1-AMPK-mTOR信号通路基因可改变细胞代谢并在癌症的恶性行为中起关键作用。因此，基于LKB1-AMPK-mTOR信号通路中的基因变异可在代谢重编程方面改变细胞内信号这一假设，本研究分析了STK11、PRKAA1、TSC1/2和mTOR基因的18个单核苷酸多态性（SNP）及其对结直肠癌患者生存的影响。
本研究纳入了772例接受手术切除的结直肠腺癌患者。基于先前的关联证据，通过计算机分析选择了18个SNP。使用SEQUENOM MassARRAY进行SNP基因分型。
在这18个多态性中，3个SNP（STK11 rs741765、PRKAA1 rs461404和TSC1 rs13295634）与无病生存期（DFS）或总生存期（OS）显著相关。在多变量分析中，STK11的GG基因型、PRKAA1的TT基因型以及TSC1的TG或GG基因型被确定为DFS较差（风险比分别为1.398、1.408和1.388；p分别为0.030、0.013和0.002）以及OS较差（风险比分别为1.431、1.680和1.394；p分别为0.038、0.001和0.009）的独立预后因素。
本研究结果表明，STK11、PRKAA1和TSC1基因的遗传变异可作为接受手术切除的结直肠癌患者的预后生物标志物。
