Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer
- Author(s)
- Mouradov, D; Sloggett, C; Jorissen, RN; Love, CG; Li, S; Burgess, AW; Arango, D; Strausberg, RL; Buchanan, D; Wormald, S; O'Connor, L; Wilding, JL; Bicknell, D; Tomlinson, IP; Bodmer, WF; Mariadason, JM; Sieber, OM;
- Details
- Publication Year 2014-04-22,Volume 74,Issue #12,Page 3238-47
- Journal Title
- Cancer Research
- Publication Type
- Journal Article
- Abstract
- Human colorectal cancer (CRC) 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 CRC 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 was compared to that published for primary CRCs in the Cancer Genome Atlas. Notably, we found that exome mutation and DNA copy-number spectra in CRC 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 epsilon (POLE) proofreading deficiency, along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGFbeta and p53 pathways. Further, we documented mutations enriched in genes involved in chromatin remodeling (ARID1A, CHD6, SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, TRRAP). Chromosomal instability was prevalent in non-hypermutated cases, with similar patterns of chromosomal gains and losses. While 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 pre-existing heterogeneity in the tumor cells. In conclusion, our results establish that human CRC lines are representative of the main subtypes of primary tumors at the genomic level, further validating their utility as tools to investigate CRC biology and drug responses.
- Publisher
- AACR
- Research Division(s)
- Systems Biology And Personalised Medicine; Structural Biology
- Publisher's Version
- https://doi.org/10.1158/0008-5472.CAN-14-0013
- Terms of Use/Rights Notice
- Copyright © 2014 American Association for Cancer Research
Creation Date: 2014-05-14 03:02:18