A Susceptibility Gene Set for Early Onset Colorectal Cancer That Integrates Diverse Signaling Pathways: Implication for Tumorigenesis

Abstract

Purpose: The causative genes for autosomal dominantly inherited familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer have been well characterized. There is, however, another 10% to 15% of early onset colorectal cancers (CRC) in which the genetic components are unclear. In this study, we used microarray technology to systematically search for differentially expressed genes in early onset CRC. Experimental Design: Young patients with non^FAP or non^hereditary nonpolyposis colorectal cancer, and healthy controls were age-(V50 years old), ethnicity-(Chinese), and tissuematched. RNAs extracted from colonic mucosa specimens were analyzed using GeneChip U133-Plus 2.0 Array. Results: Seven genes, CYR61, UCHL1, FOS, FOS B, EGR1,VIP, and KRT24, were consistently upregulated in the mucosa of all six patients compared with the mucosa from four healthy controls. The overexpression of these genes was independently validated with a testing set of six patients and six healthy controls. Principal component analysis clustered the healthy control specimens separately from the patient specimens. Real-time PCR quantification with SYBR-Green on nine other patient specimens not previously used in microarray assays confirmed the up-regulation of these seven genes. These genes function in a multitude of biological processes ranging from transcription, angiogenesis, adhesion, and inflammatory regulation to protein catabolism in various cellular compartments, from extracellular to the nucleus.They integrate known tumorigenesis (Wnt, PI3K, MAP kinase, hypoxia, G protein^coupled receptor), neurologic, insulin-signaling, and NFAT-immune pathways into an intricate biological network. Conclusions: The data suggest that the patient's mucosa is primed for tumorigenesis when cellular homeostasis is disrupted, and that the seven overexpressed genes could potentially predict early onset CRC.

Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass

“…50,51 Few of the tested markers showed decreasing transcript levels including ALIX, which was one of the most widely examined exosome markers in cancer development. 29,30,52,53 Our gene expression data correlated well with those gained from independent databases, [36][37][38][39] showing similarly reduced ALIX mRNA levels during adenoma-carcinoma sequence, which was also validated at the in situ protein level. Similar alterations between whole biopsy mRNA and protein level in epithelial compartment suggest that the majority of ALIX originated from these components.…”

“…[36][37][38][39] In adenoma vs normal comparison, results of GSE8671 data set completely supported the exosome marker mRNA level alterations revealed in analysis of our microarray data sets (Supplementary Table 2). …”

CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer

“…14,15 To the best of our knowledge, there have been no studies published focusing on the transcriptome differences in tumors from early-onset CRC patients in order to identify novel CRC susceptibility genes. Relevant to our study, Hong et al 6 have reported gene expression differences in early-onset CRC patients by comparing their normal colonic mucosa with normal colonic mucosa from healthy individuals, and identified a susceptibility gene set for early-onset CRC. Six of these seven genes were present in our data set; however, none of them were differentially expressed between the tumors from earlyand late-onset patients.…”

“…2 However, less than 5% of the cases can be ascribed to known hereditary cancer syndromes, such as familial adenomatous polyposis and Lynch syndrome, with germline mutations in high-penetrance genes (APC and DNA mismatch-repair genes, respectively). 3 Different strategies such as genetic linkage analysis, 4 DNA copy-number analysis, 5 gene expression analysis 6 and genome-wide association studies have been used to identify genetic factors that may predispose patients to cancer. 7 Interesting candidate genes have been highlighted, but the causal genetic variants underlying the increased risk remain to be identified.…”

Colorectal Neoplasia Differentially Expressed (CRNDE), a Novel Gene with Elevated Expression in Colorectal Adenomas and Adenocarcinomas

“…Data from GEO Profile GDS2609 for normal-appearing colonic mucosa (sampled >8 cm from tumor) from early-onset nonfamilial CRC patients compared with equivalent tissue from healthy individuals. 20 In the absence of any other preadenoma data, we have presented this in the adenoma columns. ) threshold above which the test outcome was deemed to be positive.…”