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

Authors' Affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore

Requests for reprints: Peh Yean Cheah, Department of Colorectal Surgery, Singapore General Hospital, Singapore 169608, Republic of Singapore. Phone: 65-6326-5365; Fax: 65-6226-2009; E-mail: cheah.peh.yean{at}sgh.com.sg.

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- (50 years old), ethnicity- (Chinese), and tissue-matched. 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 up-regulated 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.

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