Infrequently expressed miRNAs in colorectal cancer tissue and tumor molecular phenotype

• Published in: Modern pathology Vol. 30; no. 8; pp. 1152 - 1169
• Main Authors: Slattery, Martha L, Lee, Frances Y, Pellatt, Andrew J, Mullany, Lila E, Stevens, John R, Samowitz, Wade S, Wolff, Roger K, Herrick, Jennifer S
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.08.2017; Nature Publishing Group US; Elsevier Limited; Nature Publishing Group
• Subjects: 38/91; 45/90; 631/67/1857; 692/308/174; Adenocarcinoma - genetics; Adult; Aged; Case-Control Studies; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; CpG islands; Female; Gene expression; Gene Expression Profiling; Humans; K-Ras protein; Laboratory Medicine; Male; Medicine; Medicine & Public Health; MicroRNAs - analysis; MicroRNAs - biosynthesis; Microsatellite instability; Middle Aged; miRNA; Original; original-article; p53 Protein; Pathology; Phenotype; Transcriptome; Tumors
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.2017.38

We have previously shown that commonly expressed miRNAs influenced tumor molecular phenotype in colorectal cancer. We hypothesize that infrequently expressed miRNAs, when showing higher levels of expression, help to define tumor molecular phenotype. In this study, we examine 304 miRNAs expressed in at least 30 individuals, but in <50% of the population and with a mean level of expression above 1.0 relative florescent unit. We examine associations in 1893 individuals who have the tumor molecular phenotype data as well as miRNA expression levels for both carcinoma and normal colorectal tissue. We compare miRNAs uniquely associated with tumor molecular phenotype to the RNAseq data to identify genes associated with these miRNAs. This information is used to further identify unique pathways associated with tumor molecular phenotypes of TP53-mutated, KRAS-mutated, CpG island methylator phenotype and microsatellite instability tumors. Thirty-seven miRNAs were uniquely associated with TP53-mutated tumors; 30 of these miRNAs had higher level of expression in TP53-mutated tumors, while seven had lower levels of expression. Of the 34 miRNAs associated with CpG island methylator phenotype-high tumors, 16 were more likely to have a CpG island methylator phenotype-high tumor and 19 were less likely to be CpG island methylator phenotype-high. For microsatellite instability, 13 of the 22 infrequently expressed miRNAs were significantly less likely to be expressed in microsatellite unstable tumors. KRAS-mutated tumors were not associated with any miRNAs after adjustment for multiple comparisons. Of the dysregulated miRNAs, 17 were more likely to be TP53-mutated tumors while simultaneously being less likely to be CpG island methylator phenotype-high and/or microsatellite instability tumors. Genes regulated by these miRNAs were involved in numerous functions and pathways that influence cancer risk and progression. In summary, some infrequently expressed miRNAs, when expressed at higher levels, appear to have significant biological meaning in terms of tumor molecular phenotype and gene expression profiles.