title: The potential role of Alu Y in the development of resistance to SN38 (Irinotecan) or oxaliplatin in colorectal cancer.
abstract: BACKGROUND
  Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown.
  
  
  RESULTS
  We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38 or oxaliplatin resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of 'DNA methylation entropy' to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples.
  
  
  CONCLUSIONS
  Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy.
authors.affiliation: Department of Biomedicine, University of Aarhus, the Bartholin Building, DK-8000, Aarhus C, Denmark. xue.lin@biomed.au.dk.
authors.forename: Xue
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Veterinary Disease Biology, Section of Molecular Disease Biology, Faculty of Health and Medical Sciences, Copenhagen University, Strandboulevarden 49, Copenhagen, Denmark. stenvang@sund.ku.dk.
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgårdsvej 100, DK-8200, Aarhus N, Denmark. mads.heilskov@ki.au.dk.
authors.forename: Mads Heilskov
authors.initials: MH
authors.lastname: Rasmussen
authors.affiliation: BGI (Beijing Genomics Institute), Shenzhen, 518083, China. zhushida@genomics.org.cn.
authors.forename: Shida
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Veterinary Disease Biology, Section of Molecular Disease Biology, Faculty of Health and Medical Sciences, Copenhagen University, Strandboulevarden 49, Copenhagen, Denmark. nfj@sund.ku.dk.
authors.forename: Niels Frank
authors.initials: NF
authors.lastname: Jensen
authors.affiliation: Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, DK-5000, Odense C, Denmark. line.tarpgaard@rsyd.dk.
authors.forename: Line S
authors.initials: LS
authors.lastname: Tarpgaard
authors.affiliation: BGI (Beijing Genomics Institute), Shenzhen, 518083, China. yanggx@genomics.cn.
authors.forename: Guangxia
authors.initials: G
authors.lastname: Yang
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800, Lyngby, Denmark. belling@cbs.dtu.dk.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Belling
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgårdsvej 100, DK-8200, Aarhus N, Denmark. cla@ki.au.dk.
authors.forename: Claus Lindbjerg
authors.initials: CL
authors.lastname: Andersen
authors.affiliation: Department of Biomedicine, University of Aarhus, the Bartholin Building, DK-8000, Aarhus C, Denmark. jili@biomed.au.dk.|BGI (Beijing Genomics Institute), Shenzhen, 518083, China. jili@biomed.au.dk.|The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, 210096, China. jili@biomed.au.dk.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biomedicine, University of Aarhus, the Bartholin Building, DK-8000, Aarhus C, Denmark. bolund@biomed.au.dk.|BGI (Beijing Genomics Institute), Shenzhen, 518083, China. bolund@biomed.au.dk.
authors.forename: Lars
authors.initials: L
authors.lastname: Bolund
authors.affiliation: Department of Veterinary Disease Biology, Section of Molecular Disease Biology, Faculty of Health and Medical Sciences, Copenhagen University, Strandboulevarden 49, Copenhagen, Denmark. nbr@sund.ku.dk.
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
mesh_terms: D020087:Alu Elements / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin; D055747:SOX Transcription Factors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D055747:SOX Transcription Factors; D000077150:Oxaliplatin; D000077146:Irinotecan; D002166:Camptothecin