Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/12186
Title: Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.
Authors: Mouradov, Dmitri;Sloggett, Clare;Jorissen, Robert N;Love, Christopher G;Li, Shan;Burgess, Antony W;Arango, Diego;Strausberg, Robert L;Buchanan, Daniel;Wormald, Samuel;O'Connor, Liam;Wilding, Jennifer L;Bicknell, David;Tomlinson, Ian P M;Bodmer, Walter F;Mariadason, John M;Sieber, Oliver M
Affiliation: Authors' Affiliations: Ludwig Institute for Cancer Research; Systems Biology and Personalised Medicine Division; Structural Biology Division; Walter and Eliza Hall Institute of Medical Research; Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville; VLSCI Life Sciences Computation Centre, a collaboration between Melbourne, Monash and LaTrobe Universities, c/o The University of Melbourne, Carlton; Oncogenic Transcription Laboratory, Ludwig Institute for Cancer Research, Austin, VIC, Australia; Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia; Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035 Barcelona; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Spain; Ludwig Collaborative Laboratory for Cancer Biology and Therapy, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; Ludwig Institute for Cancer Research Ltd., New York, New York; Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine (WIMM), John Radcliffe Hospital, University of Oxford; and Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford, United KingdomAuthors' Affiliations: Ludwig Institute for Cancer Research; Systems Biology and Personalised Medicine Division; Structural Biology Division; Walter and Eliza Hall Institute of Medical Research; Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville; VLSCI Life Sciences Computation Centre, a collaboration between Melbourne, Monash and LaTrobe Universities, c/o The University of Melbourne, Carlton; Oncogenic Transcription Laboratory, Ludwig Institute for Cancer Research, Austin, VIC, Australia; Cancer and Population Studies
Authors' Affiliations: Ludwig Institute for Cancer Research; Systems Biology and Personalised Medicine Division; Structural Biology Division; Walter and Eliza Hall Institute of Medical Research; Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville; VLSCI Life Sciences Computation Centre, a collaboration between Melbourne, Monash and LaTrobe Universities, c/o The University of Melbourne, Carlton; Oncogenic Transcription Laboratory, Ludwig Institute for Cancer Research, Austin, VIC, Australia; Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia; Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035 Barcelona; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Spain; Ludwig Collaborative Laboratory for Cancer Biology and Therapy, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; Ludwig Institute for Cancer Research Ltd., New York, New York; Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine (WIMM), John Radcliffe Hospital, University of Oxford; and Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
Authors' Affiliations: Ludwig Institute for Cancer Research; Systems Biology and Personalised Medicine Division; Structural Biology Division; Walter and Eliza Hall Institute of Medical Research; Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville; VLSCI Life Sciences Computation Centre, a collaboration between Melbourne, Monash and LaTrobe Universities, c/o The University of Melbourne, Carlton; Oncogenic Transcription Laboratory, Ludwig Institute for Cancer Research, Austin, VIC, Australia; Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia; Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035 Barcelona; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Spain; Ludwig Collaborative Laboratory for Cancer Biology and Therapy, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; Ludwig Institute for Cancer Research Ltd., New York, New York; Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine (WIMM), John Radcliffe Hospital, University of Oxford; and Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom John.Mariadason@ludwig.edu.au Oliver.Sieber@wehi.edu.au.
Issue Date: 22-Apr-2014
Citation: Cancer Research 2014; 74(12): 3238-47
Abstract: Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, respectively. Gene expression was defined using RNA-Seq. Cell line data were compared with those published for primary colorectal cancers in The Cancer Genome Atlas. Notably, we found that exome mutation and DNA copy-number spectra in colorectal cancer cell lines closely resembled those seen in primary colorectal tumors. Similarities included the presence of two hypermutation phenotypes, as defined by signatures for defective DNA mismatch repair and DNA polymerase ε proofreading deficiency, along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGFβ, and p53 pathways. Furthermore, we documented mutations enriched in genes involved in chromatin remodeling (ARID1A, CHD6, and SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, and TRRAP). Chromosomal instability was prevalent in nonhypermutated cases, with similar patterns of chromosomal gains and losses. Although paired cell lines derived from the same tumor exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differences mainly reflected a preexisting heterogeneity in the tumor cells. In conclusion, our results establish that human colorectal cancer lines are representative of the main subtypes of primary tumors at the genomic level, further validating their utility as tools to investigate colorectal cancer biology and drug responses.
Internal ID Number: 24755471
URI: http://ahro.austin.org.au/austinjspui/handle/1/12186
DOI: 10.1158/0008-5472.CAN-14-0013
URL: http://www.ncbi.nlm.nih.gov/pubmed/24755471
Type: Journal Article
Subjects: Cell Line, Tumor
Chromosome Aberrations
Colorectal Neoplasms.genetics.metabolism
DNA Copy Number Variations
DNA Mutational Analysis
Exome
Gene Dosage
Gene Frequency
Genes, Neoplasm
Humans
Microsatellite Instability
Transcriptome
Appears in Collections:Journal articles

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