Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.

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.

[1]  V. Gebski,et al.  Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  L. Aaltonen,et al.  Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. , 1998, The New England journal of medicine.

[3]  H. Clevers,et al.  Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors , 2012, Nature.

[4]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[5]  Darryl Shibata,et al.  Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DMA mismatch repair , 1998, Nature Genetics.

[6]  V. Bohr,et al.  Involvement of Werner syndrome protein in MUTYH-mediated repair of oxidative DNA damage , 2012, Nucleic acids research.

[7]  N. Royle,et al.  The roles of WRN and BLM RecQ helicases in the Alternative Lengthening of Telomeres , 2012, Nucleic acids research.

[8]  T. Sato,et al.  The relationship of DNA ploidy to chromosomal instability in primary human colorectal cancers. , 1999, Cancer research.

[9]  I. Tomlinson,et al.  DNA polymerase ɛ and δ exonuclease domain mutations in endometrial cancer , 2013, Human molecular genetics.

[10]  Oliver Sieber,et al.  A statistical approach for detecting genomic aberrations in heterogeneous tumor samples from single nucleotide polymorphism genotyping data , 2010, Genome Biology.

[11]  David Tollervey,et al.  Coding-Sequence Determinants of Gene Expression in Escherichia coli , 2009, Science.

[12]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[13]  Michael R Hamblin,et al.  CA : A Cancer Journal for Clinicians , 2011 .

[14]  J. Herman,et al.  CpG island methylator phenotype in colorectal cancer. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[16]  Peter Donnelly,et al.  Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas , 2013, Nature Genetics.

[17]  D. Adams,et al.  PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice , 2010, Proceedings of the National Academy of Sciences.

[18]  W F Bodmer,et al.  The mutation rate and cancer. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Monnat,et al.  Spectrum and Risk of Neoplasia in Werner Syndrome: A Systematic Review , 2013, PloS one.

[20]  Keith A. Boroevich,et al.  Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators , 2012, Nature Genetics.

[21]  N. Matsubara,et al.  BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum , 2004, Gut.

[22]  Ying Liu,et al.  Analysis of P53 mutations and their expression in 56 colorectal cancer cell lines. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  D. Parkin,et al.  Global cancer statistics in the year 2000. , 2001, The Lancet. Oncology.

[24]  N. Carter,et al.  Array Comparative Genomic Hybridization Analysis of Colorectal Cancer Cell Lines and Primary Carcinomas , 2004, Cancer Research.

[25]  G. Getz,et al.  GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers , 2011, Genome Biology.

[26]  Joshua C. Gilbert,et al.  An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules , 2013, Cell.

[27]  W. Bodmer,et al.  Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel , 2012, Proceedings of the National Academy of Sciences.

[28]  G. Orphanides,et al.  Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines , 2012, BMC Medical Genomics.

[29]  M. Emond,et al.  Loss of Werner syndrome protein function promotes aberrant mitotic recombination. , 2001, Genes & development.

[30]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[31]  S Srivastava,et al.  A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. , 1998, Cancer research.

[32]  A. Rashid,et al.  Histopathological identification of colon cancer with microsatellite instability. , 2001, The American journal of pathology.

[33]  Huanming Yang,et al.  Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder , 2011, Nature Genetics.

[34]  K. Kinzler,et al.  Genetic instability in colorectal cancers , 1997, Nature.

[35]  Julie A. Wilkins,et al.  Myc deletion rescues Apc deficiency in the small intestine , 2007, Nature.

[36]  Melanie A. Huntley,et al.  Recurrent R-spondin fusions in colon cancer , 2012, Nature.

[37]  N. Carter,et al.  Refining molecular analysis in the pathways of colorectal carcinogenesis. , 2005, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[38]  Steven J. M. Jones,et al.  The genetic landscape of high-risk neuroblastoma , 2013, Nature Genetics.

[39]  W. Bodmer,et al.  5-Fluorouracil response in a large panel of colorectal cancer cell lines is associated with mismatch repair deficiency , 2010, British Journal of Cancer.

[40]  M. Adams,et al.  Recent Segmental Duplications in the Human Genome , 2002, Science.

[41]  Adam A. Margolin,et al.  The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity , 2012, Nature.

[42]  A. McCullough.  Comprehensive molecular characterization of human colon and rectal cancer , 2013 .

[43]  R. Goldsby,et al.  DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice , 2009, Proceedings of the National Academy of Sciences.

[44]  A. Duval,et al.  Comparative analysis of mutation frequency of coding and non coding short mononucleotide repeats in mismatch repair deficient colorectal cancers , 2002, Oncogene.

[45]  W. Bodmer,et al.  Mutated epithelial cadherin is associated with increased tumorigenicity and loss of adhesion and of responsiveness to the motogenic trefoil factor 2 in colon carcinoma cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  M. Siciliano,et al.  Longitudinal karyotype and genetic signature analysis of cultured human colon adenocarcinoma cell lines LS180 and LS174T. , 1980, Cancer research.

[47]  Bin Tean Teh,et al.  Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes , 2012, Nature Genetics.

[48]  P. Laird,et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer , 2006, Nature Genetics.

[49]  Y. Liu,et al.  Replication error deficient and proficient colorectal cancer gene expression differences caused by 3′UTR polyT sequence deletions , 2010, Proceedings of the National Academy of Sciences.