Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah 84108, USA.
Mol Carcinog. 2013 Feb;52(2):155-66. doi: 10.1002/mc.21841. Epub 2011 Nov 28.
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth. We evaluated the association between genetic variation in JAK1 (10 SNPs), JAK2 (9 SNPs), TYK2 (5 SNPs), suppressors of cytokine signaling (SOCS)1 (2 SNPs), SOCS2 (2 SNPs), STAT1 (16 SNPs), STAT2 (2 SNPs), STAT3 (6 SNPs), STAT4 (21 SNPs), STAT5A (2 SNPs), STAT5B (3 SNPs), STAT6 (4 SNPs) with risk of colorectal cancer. We used data from population-based case-control studies (colon cancer n = 1555 cases, 1,956 controls; rectal cancer n = 754 cases, 959 controls). JAK2, SOCS2, STAT1, STAT3, STAT5A, STAT5B, and STAT6 were associated with colon cancer; STAT3, STAT4, STAT6, and TYK2 were associated with rectal cancer. Given the biological role of the JAK/STAT-signaling pathway and cytokines, we evaluated interaction with IFNG, TNF, and IL6; numerous statistically significant associations after adjustment for multiple comparisons were observed. The following statistically significant interactions were observed: TYK2 with aspirin/NSAID use; STAT1, STAT4, and TYK2 with estrogen status; and JAK2, STAT2, STAT4, STAT5A, STAT5B, and STAT6 with smoking status and colon cancer risk; JAK2, STAT6, and TYK2 with aspirin/NSAID use; JAK1 with estrogen status; STAT2 with cigarette smoking and rectal cancer. JAK2, SOCS1, STAT3, STAT5, and TYK2 were associated with colon cancer survival (hazard rate ratio (HRR) of 3.3 95% CI 2.01,5.42 for high mutational load). JAK2, SOCS1, STAT1, STAT4, and TYK2 were associated with rectal cancer survival (HRR 2.80 95% CI 1.63,4.80). These data support the importance of the JAK/STAT-signaling pathway in colorectal cancer and suggest targets for intervention.
Janus 激酶（JAK）/信号转导子和转录激活子（STAT）信号通路参与免疫功能和细胞生长。我们评估了 JAK1（10 个 SNP）、JAK2（9 个 SNP）、TYK2（5 个 SNP）、细胞因子信号转导抑制剂（SOCS）1（2 个 SNP）、SOCS2（2 个 SNP）、STAT1（16 个 SNP）、STAT2（2 个 SNP）、STAT3（6 个 SNP）、STAT4（21 个 SNP）、STAT5A（2 个 SNP）、STAT5B（3 个 SNP）、STAT6（4 个 SNP）中的遗传变异与结直肠癌风险之间的关联。我们使用了基于人群的病例对照研究的数据（结肠癌 n=1555 例，1956 例对照；直肠癌 n=754 例，959 例对照）。JAK2、SOCS2、STAT1、STAT3、STAT5A、STAT5B 和 STAT6 与结肠癌相关；STAT3、STAT4、STAT6 和 TYK2 与直肠癌相关。鉴于 JAK/STAT 信号通路和细胞因子的生物学作用，我们评估了与 IFNG、TNF 和 IL6 的相互作用；在进行多次比较调整后，观察到许多具有统计学意义的关联。观察到以下具有统计学意义的相互作用：TYK2 与阿司匹林/非甾体抗炎药的使用；STAT1、STAT4 和 TYK2 与雌激素状态；JAK2、STAT2、STAT4、STAT5A、STAT5B 和 STAT6 与吸烟状况和结肠癌风险；JAK2、STAT6 和 TYK2 与阿司匹林/非甾体抗炎药的使用；JAK1 与雌激素状态；STAT2 与吸烟和直肠癌。JAK2、SOCS1、STAT3、STAT5 和 TYK2 与结肠癌的生存相关（高突变负荷的危险率比（HRR）为 3.3，95%CI 为 2.01，5.42）。JAK2、SOCS1、STAT1、STAT4 和 TYK2 与直肠癌的生存相关（HRR 为 2.80，95%CI 为 1.63，4.80）。这些数据支持 JAK/STAT 信号通路在结直肠癌中的重要性，并提示了干预的靶点。
