DCC – Colorectal Cancer

Deleted in Colorectal Cancer (DCC) encodes a netrin-1 receptor involved in cell–cell adhesion and axon guidance. Somatic alterations of DCC are a hallmark of colorectal carcinoma and implicate it as a tumor suppressor (PMID:1469893, [PMID:1469893]).

Early genetic studies reported frequent allelic deletions on chromosome 18q targeting DCC in colorectal tumors. LOH at the DCC locus was observed in 60% (15/25) of carcinomas (PMID:8846166) and microsatellite analysis detected DCC deletions in 41% of informative cases (PMID:7860623). Point mutations at codon 201 (c.602G>A (p.Arg201Gln)) were found in 53% (8/15) of tumors with either mutation or LOH of the wild-type allele (PMID:9484816).

Functional assays confirmed that DCC mRNA was reduced in 57% (8/14) of colorectal carcinomas by RT-PCR (PMID:1306299), and immunohistochemistry showed loss of DCC protein in 69% (11/16) of tumors, correlating with LOH and codon 201 mutation (PMID:9484816).

In stage I–II disease, DCC LOH was present in 12% (5/43) of cases and was associated with more aggressive features when combined with K-RAS codon 12 mutations (PMID:17410283).

Mechanistic data support a haploinsufficiency model: loss of DCC disrupts netrin-1 signaling and cell–cell adhesion, promoting neoplastic growth in colonic epithelium. In vitro, DCC loss correlates with increased proliferation and reduced differentiation of CRC cells.

Although some cohorts report lower frequencies in early or proximal tumors (PMID:7860623), the preponderance of evidence demonstrates recurrent DCC inactivation in CRC. This underpins its utility as a diagnostic and prognostic biomarker and a potential therapeutic target in colorectal cancer.

Key take-home sentence: Frequent somatic loss and reduced expression of DCC in colorectal cancer confirm its tumor suppressor role and support its clinical application in prognosis and targeted therapy.

References

• Journal of cellular biochemistry. Supplement • 1992 • Suppressor gene alterations in the colorectal adenoma-carcinoma sequence. PMID:1469893
• Journal of cancer research and clinical oncology • 1995 • Low frequency and late occurrence of p53 and dcc aberrations in colorectal tumours. PMID:7860623
• British journal of cancer • 1998 • Detection of the DCC gene product in normal and malignant colorectal tissues and its relation to a codon 201 mutation. PMID:9484816
• The Tohoku journal of experimental medicine • 1992 • Mutations of the p53 gene and other genes involving in human colorectal carcinogenesis. PMID:1306299
• Journal of molecular medicine (Berlin, Germany) • 1996 • Lower frequency of allele loss on chromosome 18q in human breast cancer than in colorectal tumors. PMID:8846166
• Journal of gastrointestinal and liver diseases : JGLD • 2007 • Clinical significance of p53, K-ras and DCC gene alterations in the stage I-II colorectal cancers. PMID:17410283

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