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

Stephen J. O'Brien, Theodore Kalbfleisch, Sudhir Srivastava, Jianmin Pan, Shesh Rai, Robert E. Petras, Nemencio Ronquillo, Hiram C. Polk, Susan Galandiuk

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


BACKGROUND: Colon cancer survival is dependent on metastatic potential and treatment. Large RNA-sequencing data sets may assist in identifying colon cancer-specific biomarkers to improve patient outcomes. OBJECTIVE: This study aimed to identify a highly specific biomarker for overall survival in colon adenocarcinoma by using an RNA-sequencing data set. DESIGN: Raw RNA-sequencing and clinical data for patients with colon adenocarcinoma (n = 271) 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 US accredited cancer centers between 1998 and 2013 were analyzed. MAIN OUTCOME MEASURES: The primary outcome measures were recurrence-free and overall survival. RESULTS: The median age was 66 years (147/271 men, 180/271 White patients). Thirty RNAs were differentially expressed in colon adenocarcinoma compared with paired normal epithelium, using a log-fold change cutoff of ±6. Using median expression as a cutoff, 4 RNAs were associated with worse overall survival: decreased ZG16 (log-rank = 0.023), aquaporin 8 (log-rank = 0.023), and SLC26A3 (log-rank = 0.098), and increased COL1A1 (log-rank = 0.105). On multivariable analysis, low aquaporin 8 expression (HR, 1.748; 95% CI, 1.016-3.008; p = 0.044) was a risk factor for worse overall survival. Our final aquaporin 8 model had an area under the curve of 0.85 for overall survival. On subgroup analysis, low aquaporin 8 was associated with worse overall survival in patients with high microsatellite instability and in patients with stage II disease. Low aquaporin 8 expression was associated with KRAS and BRAF mutations. Aquaporin 8 immunohistochemistry was optimized for clinical application. LIMITATIONS: This was a retrospective study. CONCLUSION: Aquaporin 8 is a water channel selectively expressed in normal colon tissue. Low aquaporin 8 expression is a risk factor for worse overall survival in patients who have colon cancer. Aquaporin 8 measurement may have a role as a colon-specific prognostic biomarker and help in patient risk stratification for increased surveillance. See Video Abstract at

Original languageEnglish
Pages (from-to)1083-1095
Number of pages13
JournalDiseases of the Colon and Rectum
Issue number9
StatePublished - Sep 1 2021

Bibliographical note

Funding Information:
Funding/Support: This work was supported by the John W. Price and Barbara Thruston Atwood Price Trust and a grant from the Mary K. Oxley Foundation.

Publisher Copyright:
© Copyright The American Society of Colon & Rectal Surgeons, Inc.


  • Aquaporin 8
  • Colon cancer
  • Overall survival
  • RNA-sequencing

ASJC Scopus subject areas

  • Gastroenterology


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