Colorectal Cancer Cell Lines Are Representative Models of the Main Molecular Subtypes of Primary Cancer

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. Cancer Res; 74(12); 3238–47. ©2014 AACR.

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

“…Several studies show that CRC cell lines recapitulate the main molecular phenotypes observed in primary CRC (Ahmed et al ., 2013; Barretina et al ., 2012; Berg et al ., 2017; Medico et al ., 2015; Mouradov et al ., 2014), which substantiate their value as preclinical model systems to assess a variety of pharmacogenomic relationships. Consistent with the observed clinical benefit in patients with CDX2‐negative tumors in stage III, loss of CDX2 expression was strongly associated with sensitivity to conventional chemotherapeutics in vitro , both in our drug screen dataset and in a large public dataset, again independent of MSI status.…”

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

“…We also observed that the rare hypermutator/ MSI-negative subgroup, identified in about 2% of CRC cases, is represented by three lines, HT115, HCC2998 and HT55 (ref. 16). …”

“…Accordingly, precision oncology depends on the ability to functionally interrogate preclinical models capturing the molecular heterogeneity observed in patients. While collections of cancer cells derived from multiple tumor types have been previously described 1,2,4 , comprehensive databases of cells derived from single tumour lineages are much less common 16,31 . To capture the clinical heterogeneity of CRCs, we assembled a collection of 151 cell lines.…”

Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

“…4A). Interestingly, the T173I mutation was found in RUNX3 in the colon carcinoma cell line LS411, whereas its equivalent mutation in RUNX1 (T196I) was detected in chronic myelomonocytic leukemia (cancer.sanger.ac.uk/cosmic) (23)(24)(25); the equivalent residue in RUNX2 was found to be mutated, also to isoleucine, in the disease cleidocranial dysplasia (CCD) (26). This finding indicates that the T173 residue is important for the function of the Runt domain.…”