Lower Expression of CFTR Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer

SIMPLE SUMMARY: The ion channel gene CFTR is a tumor suppressor in colorectal cancer. It is well-established that individuals with cystic fibrosis, caused by biallelic germline mutations in CFTR, are at increased risk of developing colorectal cancer. A population of colorectal cancer patients with no known relationship to cystic fibrosis expresses reduced levels of CFTR in their tumors. This study aimed to determine if this population experienced increased mortality compared to those expressing higher levels of CFTR. Three independent datasets containing 1177 colorectal cancer patients were analyzed using Cox proportional hazards regression. Analysis of each study individually and meta-analysis of all three revealed an association between reduced CFTR expression and increased mortality. This association is potentially clinically significant because individuals with low CFTR expression may benefit from more aggressive treatment. Additionally, molecular therapies developed to treat cystic fibrosis by increasing CFTR activity may be applicable for colorectal cancer tumors expressing low levels of CFTR. ABSTRACT: Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), 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 CFTR mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced CFTR expression in this population, we investigated association of tumoral CFTR expression with overall and disease-specific mortality in CRC patients. CFTR 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] CFTR 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 CFTR expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, CFTR 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 CFTR expression, (p-interaction: 0.06). The findings from these three datasets support the hypothesis that low CFTR expression is associated with increased CRC mortality.