Decreased Tumoral Expression of Colon-Specific Water Channel Aquaporin 8 Is Associated With Reduced Overall Survival in Colon Adenocarcinoma.

BACKGROUND Colon cancer survival is dependent upon metastatic potential and treatment. Large RNA-sequencing datasets may assist in identifying colon cancer-specific biomarkers to improve patient outcomes. OBJECTIVE To identify a highly specific biomarker for overall survival in colon adenocarcinoma using an RNA-sequencing data set. DESIGN Raw RNA-sequencing and clinical data for patients with colon adenocarcinoma (n=269) were downloaded from The Cancer Genome Atlas. A binomial regression model was used to calculate differential RNA expression between paired colon cancer and normal epithelium samples (n=40). Highly differentially expressed RNAs were examined. SETTINGS This study was conducted at the University of Louisville using data acquired by The Cancer Genome Atlas. PATIENTS Patients from United States accredited cancer centers between 1998-2013 were analyzed. MAIN OUTCOME MEASURES The primary outcome measures were recurrence-free and overall survival. RESULTS The median age was 66 years (147/269 men, 180/269 Caucasian). Thirty RNAs were differentially expressed in colon adenocarcinoma compared to paired normal epithelium, using a log fold change cutoff of ±6. Using median expression as a cutoff, four RNAs were associated with worse overall survival: decreased ZG16 (log-rank=0.023), aquaporin8 (log-rank=0.023), and SLC26A3 (log-rank=0.098), and increased COL1A1(log-rank=0.105). On multivariable analysis, low aquaporin8 expression (HR=1.748, 95% CI: 1.016-3.008, p=0.044) was a risk factor for worse overall survival. Our final aquaporin8 model had an AUC of 0.85 for overall survival. On subgroup analysis, low aquaporin8 was associated with worse overall survival in MSI-H patients, and in stage II patients. Low aquaporin8 expression was associated with KRAS and BRAF mutations. Aquaporin8 immunohistochemistry was optimized for clinical application. LIMITATIONS This was a retrospective study. CONCLUSION Aquaporin8 is a water channel selectively expressed in normal colon tissue. Low AQP8 expression is a risk factor for worse overall survival in colon cancer patients. Aquaporin8 measurement may have a role as a colon-specific prognostic biomarker and help in patient risk stratification for increased surveillance.