title: Alternative cleavage and polyadenylation during colorectal cancer development.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Netherlands Cancer Institute, The Netherlands.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Morris
authors.forename: Arnold
authors.initials: A
authors.lastname: Bos
authors.forename: Begoña
authors.initials: B
authors.lastname: Diosdado
authors.forename: Koos
authors.initials: K
authors.lastname: Rooijers
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bolijn
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002448:Cell Adhesion / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D026723:Polyadenylation / Q000235:genetics; D059367:RNA Cleavage / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D012333:RNA, Messenger