CDX2is an amplified lineage-survival oncogene in colorectal cancer

Abstract

The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such as MYC and RAS, are active across many different cancer types. In contrast, "lineage-survival" oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, we identify recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor 2 (CDX2), a regulator of normal intestinal lineage development and differentiation, as a target of the amplification. In contrast to its described role as a colorectal tumor suppressor, CDX2 when amplified is required for the proliferation and survival of colorectal cancer cells. Further, transcriptional profiling, binding-site analysis, and functional studies link CDX2 to Wnt/β-catenin signaling, itself a key oncogenic pathway in colorectal cancer. These data characterize CDX2 as a lineage-survival oncogene deregulated in colorectal cancer. Our findings challenge a prevailing view that CDX2 is a tumor suppressor in colorectal cancer and uncover an additional piece in the multistep model of colorectal tumorigenesis.lineage dependency | lineage-addiction oncogene | 13q amplification | CDK8 | integrative genomics

Gene‐dosage dependent overexpression at the 13q amplicon identifies DIS3 as candidate oncogene in colorectal cancer progression

“…Other candidate oncogenes residing at 13q include CDX2 and CDK8, both functionally linked to WNT/bcatenin signaling (Firestein et al, 2008;Salari et al, 2012). CDX2 is required for proliferation and survival of CRC cells and CDK8 acts by driving b-catenin activity and has a role in maintaining tumor and embryonic stem cell differentiation states through regulation of MYC (Firestein et al, 2008;Adler et al, 2012;Salari et al, 2012). Together with our results these findings support the hypothesis that multiple genes activated through amplification of chromosome 13q are involved in critical pathways in CRC carcinogenesis.…”

The clinical perspectives of CDX2 expression in colorectal cancer: A qualitative systematic review

“…Supporting that down-regulation of CDX2 might be of importance in tumor progression, is evidence of a poorer outcome in those patients with loss of CDX2 expression in their tumors [37,43,48]. For chromosomal instability tumors, it might be the case, that they are partly reliant on CDX2 expression and that the gene in some cases is amplified and up-regulated [28,64,80]. This is supported by cell line experiments showing that in several colon cancer cell lines, it is impossible to knock-down CDX2 completely and keep the cells viable [64,81,82].…”

“…This was seen in 50% of cases of colorectal cancers investigated [64]. Further investigations showed that this amplification were only significant in colorectal derived tumors and not other cancer forms, emphasizing its linage specific function.…”

CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer

“…Sixty percent of colon cancers arise from the CIN pathway and are distinguished by aneuploidy and recurrent chromosomal amplifications at distinct genomic loci. A number of tumor-suppressor genes (APC, 5q21; DCC, 18q21) and oncogenes (cMYC, 8q24; MET, 7q; CDK8, CDX2, 13q; PRPF6, 20q) have been shown to reside in these regions of copy number alterations (8)(9)(10)(11)(12)(13).…”