Abstract
Selecting colorectal cancer (CRC) patients likely to respond to therapy remains a clinical challenge. The objectives of this study were to establish which genes were differentially expressed with respect to treatment sensitivity and relate this to copy number in a panel of 15 CRC cell lines. Copy number variations of the identified genes were assessed in a cohort of CRCs. IC50’s were measured for 5-fluorouracil, oxaliplatin, and BEZ-235, a PI3K/mTOR inhibitor. Cell lines were profiled using array comparative genomic hybridisation, Illumina gene expression analysis, reverse phase protein arrays, and targeted sequencing of KRAS hotspot mutations. Frequent gains were observed at 2p, 3q, 5p, 7p, 7q, 8q, 12p, 13q, 14q, and 17q and losses at 2q, 3p, 5q, 8p, 9p, 9q, 14q, 18q, and 20p. Frequently gained regions contained EGFR, PIK3CA, MYC, SMO, TRIB1, FZD1, and BRCA2, while frequently lost regions contained FHIT and MACROD2. TRIB1 was selected for further study. Gene enrichment analysis showed that differentially expressed genes with respect to treatment response were involved in Wnt signalling, EGF receptor signalling, apoptosis, cell cycle, and angiogenesis. Stepwise integration of copy number and gene expression data yielded 47 candidate genes that were significantly correlated. PDCD6 was differentially expressed in all three treatment responses. Tissue microarrays were constructed for a cohort of 118 CRC patients and TRIB1 and MYC amplifications were measured using fluorescence in situ hybridisation. TRIB1 and MYC were amplified in 14.5% and 7.4% of the cohort, respectively, and these amplifications were significantly correlated (p≤0.0001). TRIB1 protein expression in the patient cohort was significantly correlated with pERK, Akt, and Caspase 3 expression. In conclusion, a set of candidate predictive biomarkers for 5-fluorouracil, oxaliplatin, and BEZ235 are described that warrant further study. Amplification of the putative oncogene TRIB1 has been described for the first time in a cohort of CRC patients.
Highlights
Colorectal cancer (CRC) accounts for 8% of all cancer deaths [1], with variable survival of between 39% and 65% depending on stage at diagnosis [2]
After treatment with 5-fluorouracil (5-FU) for 96 h, thirteen CRC cell lines showed varying degrees of sensitivity when treated with drug concentrations ranging from 2.5μM to 100μM (Fig 1A)
This study suggested that suppressing programmed cell death 6 (PDCD6) supports tumorigenesis by inhibiting apoptosis in ovarian cancer [67]
Summary
Colorectal cancer (CRC) accounts for 8% of all cancer deaths [1], with variable survival of between 39% and 65% depending on stage at diagnosis [2]. The major pathways implicated in colorectal carcinogenesis include, but are not limited to, the PI3K/mTOR pathway, the mitogen-activated protein kinases (MAPK) pathway, and the Wnt pathway [4], with the JAK/STAT pathway, Hedgehog pathway, and NFκB pathway involved [5]. These pathways are controlled via complex crosstalk, negative feedback, and other compensatory mechanisms. The most frequently mutated genes in CRC are APC (70–80%), TP53 (50%), KRAS (35–45%), PIK3CA (25–32%), BRAF (10–17%) and PTEN (4–5%) [7,8,9,10,11,12]
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