Abstract
Alternative cleavage and polyadenylation (APA) of mRNAs is a phenomenon that alters 3'-untranslated region length leading to altered posttranscriptional regulation of gene expression. Changing APA patterns have been shown to result in misregulation of genes involved in carcinogenesis; therefore, we hypothesized that altered APA contributes to progression of colorectal cancer, and that measurement of APA may lead to discovery of novel biomarkers. We used next-generation sequencing to directly measure global patterns of APA changes during colorectal carcinoma progression in 15 human patient samples. Results were validated in a larger cohort of 50 patients, including 5 normal/carcinoma pairs from individuals. We discovered numerous genes presenting progressive changes in APA. Genes undergoing untranslated region (3'UTR) shortening were enriched for functional groups such as cell-cycle and nucleic acid-binding and processing factors, and those undergoing 3'UTR lengthening or alternative 3'UTR usage were enriched for categories such as cell-cell adhesion and extracellular matrix. We found indications that APA changes result from differential processing of transcripts because of increased expression of cleavage and polyadenylation factors. Quantitative PCR analysis in a larger series of human patient samples, including matched pairs, confirmed APA changes in DMKN, PDXK, and PPIE genes. Our results suggest that genes undergoing altered APA during human cancer progression may be useful novel biomarkers and potentially targeted for disease prevention and treatment. We propose that the strategy presented here may be broadly useful in discovery of novel biomarkers for other types of cancer and human disease.
Highlights
Colorectal cancer (CRC) is the second most common cause of cancer death in the Western world and a major health care problem [1]
Genes undergoing untranslated region (30UTR) shortening were enriched for functional groups such as cell-cycle and nucleic acid–binding and processing factors, and those undergoing 30-untranslated region (30UTR) lengthening or alternative 30UTR usage were enriched for categories such as cell–cell adhesion and extracellular matrix
We found indications that APA changes result from differential processing of transcripts because of increased expression of cleavage and polyadenylation factors
Summary
Colorectal cancer (CRC) is the second most common cause of cancer death in the Western world and a major health care problem [1]. Decreased CRC mortality can be achieved by identification of novel diagnostic, predictive, and prognostic biomarkers and the development of new therapies. Most of the studies concerning identification of biomarkers in CRC have mainly focused on known molecular pathways and aberrations (i.e., mutation, methylation changes, DNA copy number alterations, and microRNAs) contributing to CRC pathogenesis [2,3,4,5,6]. Conducting unbiased genome wide studies based on novel. Authors' Affiliations: 1Division of Gene Regulation, The Netherlands Cancer Institute; 2Department of Pathology VU Medical Centre, Amsterdam; and 3The Centre for Biomedical Genetics, The Netherlands. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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