| Summary: | Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (<i>CFTR)</i>, 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 <i>CFTR</i> mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced <i>CFTR</i> expression in this population, we investigated association of tumoral <i>CFTR</i> expression with overall and disease-specific mortality in CRC patients. <i>CFTR</i> 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] <i>CFTR</i> 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 <i>CFTR</i> expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, <i>CFTR</i> 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 <i>CFTR</i> expression, (<i>p</i>-interaction: 0.06). The findings from these three datasets support the hypothesis that low <i>CFTR</i> expression is associated with increased CRC mortality.
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