Scott Patricia, Wang Shuo, Onyeaghala Guillaume, Pankratz Nathan, Starr Timothy, Prizment Anna E
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA.
Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA.
Cancers (Basel). 2023 Feb 3;15(3):989. doi: 10.3390/cancers15030989.
Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (, have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced expression in this population, we investigated association of tumoral expression with overall and disease-specific mortality in CRC patients. mRNA expression, clinical factors and survival data from 1177 CRC patients reported in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus studies GSE39582 and GSE17538 were included. Log-transformed and z-normalized [mean = 0, standard deviation (SD) = 1] expression values were modeled as quartiles or dichotomized at the median. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific mortality in individual studies and meta-analyses. Analyses of each of the three individual datasets showed a robust association of decreased expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, expression was inversely associated with risk of overall death [pooled HR (95% CI): 0.70 (0.57-0.86)] and disease-specific death [pooled HR (95% CI): 0.68 (0.47-0.99)]. Associations did not differ by stage at diagnosis, age, or sex. Meta-analysis of overall death stratified by microsatellite instable (MSI) versus microsatellite stable (MSS) status indicated potential interaction between MSI/MSS status and expression, (-interaction: 0.06). The findings from these three datasets support the hypothesis that low expression is associated with increased CRC mortality.
由囊性纤维化跨膜传导调节因子（CFTR）的双等位基因种系突变引起的囊性纤维化（CF）患者患结直肠癌（CRC）的风险更高且发病更早。非CF人群中的一部分CRC患者肿瘤CFTR mRNA表达水平较低，这也可能导致CFTR活性降低。为了确定该人群中CFTR表达降低的后果，我们研究了肿瘤CFTR表达与CRC患者总死亡率和疾病特异性死亡率的相关性。纳入了癌症基因组图谱（TCGA）以及基因表达综合数据库研究GSE39582和GSE17538中报告的1177例CRC患者的CFTR mRNA表达、临床因素和生存数据。将对数转换和z标准化[均值 = 0，标准差（SD）= 1]的CFTR表达值建模为四分位数或在中位数处进行二分法划分。使用单变量和多变量Cox比例风险回归模型来估计各个研究和荟萃分析中总死亡率和疾病特异性死亡率的风险比（HR）和95%置信区间（CI）。对三个独立数据集的每项分析均显示CFTR表达降低与死亡率增加之间存在密切关联。在针对诊断分期、年龄和性别进行调整的荟萃分析中，CFTR表达与总死亡风险呈负相关[合并HR（95%CI）：0.70（0.57 - 0.86）]以及与疾病特异性死亡风险呈负相关[合并HR（95%CI）：0.68（0.47 - 0.99）]。相关性在诊断分期、年龄或性别方面无差异。按微卫星不稳定（MSI）与微卫星稳定（MSS）状态分层的总死亡荟萃分析表明MSI/MSS状态与CFTR表达之间存在潜在相互作用（P相互作用：0.06）。这三个数据集的研究结果支持低CFTR表达与CRC死亡率增加相关的假设。
