Infrequently expressed miRNAs influence survival after diagnosis with colorectal cancer

// Martha L. Slattery 1 , Andrew J. Pellatt 2 , Frances Y. Lee 2 , Jennifer S. Herrick 3 , Wade S. Samowitz 4 , John R. Stevens 5 , Roger K. Wolff 6 and Lila E. Mullany 7 1 Department of Medicine, University of Utah, Salt Lake City, Utah, USA 2 Tulane Medical School, New Orleans, Louisiana, USA 3 Department of Medicine, University of Utah, Salt Lake City, Utah, USA 4 Department of Pathology, University of Utah, Salt Lake City, Utah, USA 5 Department of Mathematics and Statistics, Utah State University, Logan, Utah, USA 6 Department of Medicine, University of Utah, Salt Lake City, Utah, USA 7 Department of Medicine, University of Utah, Salt Lake City, Utah, USA Correspondence to: Martha L. Slattery, email: marty.slattery@hsc.utah.edu Keywords: colorectal cancer, miRNAs, survival, stage, prognosis Received: May 16, 2017      Accepted: July 25, 2017      Published: August 03, 2017 ABSTRACT Half of miRNAs expressed in colorectal tissue are expressed < 50% of the population. Many infrequently expressed miRNAs have low levels of expression. We hypothesize that less frequently expressed miRNAs, when expressed at higher levels, influence both disease stage and survival after diagnosis with colorectal cancer (CRC); low levels of expression may be background noise. We examine 304 infrequently expressed miRNAs in 1893 population-based cases of CRC with paired carcinoma and normal mucosa miRNA profiles. We evaluate miRNAs with disease stage and survival after adjusting for age, study center, sex, MSI status, and AJCC stage. These miRNAs were further evaluated with RNA-Seq data to identify miRNA::mRNA associations that may provide insight into the functionality of miRNAs. Eleven miRNAs were associated with advanced disease stage among colon cancer patients ( Q value = 0.10). Eight infrequently expressed miRNAs influenced survival if highly expressed in overall CRC. Of these, five increased likelihood of dying if they were highly expressed, i.e. miR-124-3p, miR-143-5p, miR-145-3p, miR31-5p, and miR-99b-5p, while three were associated with better survival if highly expressed, i.e. miR-362-5p, miR-374a-5p, and miR-590-5p. Thirteen miRNAs infrequently expressed in colon-specific carcinoma tissue were associated with CRC survival if highly expressed. Evaluation of miRNAs::mRNA associations showed that mRNA expression influenced by infrequently expressed miRNA contributed to networks and pathways shown to influence disease progression and prognosis. Our large study enabled us to examine the implications of infrequently expressed miRNAs after removal of background noise. These results require replication in other studies. Confirmation of our findings in other studies could lead to important markers for prognosis.