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

Dmitri Mouradov, Clare Sloggett, Robert Jorissen, Christopher G. Love, Shan Li, Antony W. Burgess, Diego Arango, Robert L. Strausberg, Daniel Buchanan, Samuel Wormald, Liam O'Connor, Jennifer L. Wilding, David Bicknell, Ian P.M. Tomlinson, Walter F. Bodmer, John M. Mariadason, Oliver M. Sieber

Research output: Contribution to journalArticle

148 Citations (Scopus)

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 de fined 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.

LanguageEnglish
Pages3238-3247
Number of pages10
JournalCancer Research
Volume74
Issue number12
DOIs
Publication statusPublished - 15 Jun 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mouradov, Dmitri ; Sloggett, Clare ; Jorissen, Robert ; 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. / Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. In: Cancer Research. 2014 ; Vol. 74, No. 12. pp. 3238-3247.
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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 de fined 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.",
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Mouradov, D, Sloggett, C, Jorissen, R, Love, CG, Li, S, Burgess, AW, Arango, D, Strausberg, RL, Buchanan, D, Wormald, S, O'Connor, L, Wilding, JL, Bicknell, D, Tomlinson, IPM, Bodmer, WF, Mariadason, JM & Sieber, OM 2014, 'Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer', Cancer Research, vol. 74, no. 12, pp. 3238-3247. https://doi.org/10.1158/0008-5472.CAN-14-0013

Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. / Mouradov, Dmitri; Sloggett, Clare; Jorissen, Robert; 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.

In: Cancer Research, Vol. 74, No. 12, 15.06.2014, p. 3238-3247.

Research output: Contribution to journalArticle

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T1 - Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer

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AU - Sloggett, Clare

AU - Jorissen, Robert

AU - Love, Christopher G.

AU - Li, Shan

AU - Burgess, Antony W.

AU - Arango, Diego

AU - Strausberg, Robert L.

AU - Buchanan, Daniel

AU - Wormald, Samuel

AU - O'Connor, Liam

AU - Wilding, Jennifer L.

AU - Bicknell, David

AU - Tomlinson, Ian P.M.

AU - Bodmer, Walter F.

AU - Mariadason, John M.

AU - Sieber, Oliver M.

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