MicroRNAs (miRNA) are a class of small regulatory RNAs that mediate post-transcriptional silencing of specific target mRNAs. Our overall hypotheses are that miRNA expression is unique to tumor molecular phenotype;that miRNA expression levels at time of diagnosis predicts survival;and that miRNA expression is associated with inflammation-related genetic and lifestyle factors key to colorectal cancer (CRC). This study takes a two pronged approach to addressing our hypotheses. While we propose to validate previously identified miRNAs that have been identified as associated with CRC (either by differential expression or from assessment of mutations), we will add to the field through discovery of new and important associations that may be unique to specific molecular phenotypes, to polyp to cancer progression, and to survival. We will analyze the expression of 866 human miRNAs using data derived from tumor and paired normal tissue at time of diagnosis from: 1660 people with incident colon cancer;840 people with incident rectal cancer;and 350 polyps from our colon and rectal cases who reported a prior polyp;5% of tumors, will be analyzed for quality control. Our total assessment will be on 5475 samples. We will extend the validation of previously identified mutated miRNAs and differentially expressed miRNAs to determine if these alterations are associated with specific tumor molecular phenotype, inflammation-related factors, clinical factors and survival. Important miRNAs will be validated using TaqMan-based assays. Associations will be tested based on differential expression for both individual and groups of miRNAs using recent extensions of several statistical methods including ANOVA, logistic regression, and Cox proportional hazards models. Our sample size allows for both a training and validation component, and provides sufficient statistical power to meet the study goals. MiRNAs that are differentially expressed in polyps and in subsequent tumors will provide new insights into targets for screening and treatment and differential miRNAs that function as the """"""""driver"""""""" vs. the """"""""passenger"""""""" in the carcinogenic process. Testing of mutated miRNAs identified from sequencing in conjunction with tumor phenotype, clinical, and survival data will further validate the importance of these miRNAs, and provide insight as to which CRC molecular pathway the miRNAs function. Our rich dataset of lifestyle, genetic, clinical and prognosis, and tumor molecular phenotype on 2500 CRC and paired normal tissue allows us to examine factors that are associated with miRNAs in a large set of population-based cases. The miRNAs identified in these analyses will elucidate pathways important in the etiology of CRC and will provide insight into potential targets for screening and treatment.

Public Health Relevance

Our rich dataset of lifestyle, genetic, clinical and prognosis, and tumor molecular phenotype on 2500 CRC (colorectal cancer) and paired normal tissue allows us to examine factors that are associated with miRNA expression and mutation in a large sample of population-based cases. Having data available on polyps from those cases who developed cancer, will help us determine drivers vs. passengers in the carcinogenic process. The miRNAs identified in these analyses will elucidate pathways important in the etiology of CRC and will provide insight into potential targets for screening and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163683-03
Application #
8686601
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Umar, Asad
Project Start
2012-09-08
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Slattery, Martha L; Herrick, Jennifer S; Stevens, John R et al. (2017) An Assessment of Database-Validated microRNA Target Genes in Normal Colonic Mucosa: Implications for Pathway Analysis. Cancer Inform 16:1176935117716405
Slattery, Martha L; Pellatt, Andrew J; Lee, Frances Y et al. (2017) Infrequently expressed miRNAs influence survival after diagnosis with colorectal cancer. Oncotarget 8:83845-83859
Slattery, Martha L; Lee, Frances Y; Pellatt, Andrew J et al. (2017) Infrequently expressed miRNAs in colorectal cancer tissue and tumor molecular phenotype. Mod Pathol 30:1152-1169
Mullany, Lila E; Herrick, Jennifer S; Wolff, Roger K et al. (2017) Single nucleotide polymorphisms within MicroRNAs, MicroRNA targets, and MicroRNA biogenesis genes and their impact on colorectal cancer survival. Genes Chromosomes Cancer 56:285-295
Mullany, Lila E; Herrick, Jennifer S; Wolff, Roger K et al. (2017) Transcription factor-microRNA associations and their impact on colorectal cancer survival. Mol Carcinog 56:2512-2526
Campbell, Peter T; Rebbeck, Timothy R; Nishihara, Reiko et al. (2017) Proceedings of the third international molecular pathological epidemiology (MPE) meeting. Cancer Causes Control 28:167-176
Mullany, Lila E; Herrick, Jennifer S; Wolff, Roger K et al. (2017) Alterations in microRNA expression associated with alcohol consumption in rectal cancer subjects. Cancer Causes Control 28:545-555
Slattery, Martha L; Herrick, Jennifer S; Wolff, Roger K et al. (2017) The miRNA landscape of colorectal polyps. Genes Chromosomes Cancer 56:347-353
Slattery, Martha L; Herrick, Jennifer S; Mullany, Lila E et al. (2017) The co-regulatory networks of tumor suppressor genes, oncogenes, and miRNAs in colorectal cancer. Genes Chromosomes Cancer 56:769-787
Mullany, Lila E; Herrick, Jennifer S; Wolff, Roger K et al. (2017) MicroRNA-transcription factor interactions and their combined effect on target gene expression in colon cancer cases. Genes Chromosomes Cancer :

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