Early Detection Research Network

Deleted in colorectal cancer is a putative conditional tumor-suppressor gene inactivated by promoter hypermethylation in head and neck squamous cell carcinoma.

Deleted in colorectal cancer (DCC) is a candidate tumor-suppressor gene located at chromosome 18q21. However, DCC gene was found to have few somatic mutations and the heterozygous mice (DCC(+/-)) showed a similar frequency of tumor formation compared with the wild-type mice (DCC(+/+)). Recently, DCC came back to the spotlight as a better understating of its function and relationship with its ligand (netrin-1) had shown that DCC may act as a conditional tumor-suppressor gene. We evaluated hypermethylation as a mechanism for DCC inactivation in head and neck squamous cell carcinoma (HNSCC). DCC promoter region hypermethylation was found in 75% of primary HNSCC. There was a significant correlation between DCC promoter region hypermethylation and DCC expression (assessed by immunohistochemistry; P = 0.021). DCC nonexpressing HNSCC cell lines JHU-O12 and JHU-O19 with baseline hypermethylation of the DCC promoter were treated with 5-aza-2'-deoxycytidine (a demethylating agent) and reexpression of DCC was noted. Transfection of DCC into DCC-negative HNSCC cell lines resulted in complete abrogation of growth in all cell lines, whereas additional cotransfection of netrin-1 resulted in rescue of DCC-mediated growth inhibition. These results suggest that DCC is a putative conditional tumor-suppressor gene that is epigenetically inactivated by promoter hypermethylation in a majority of HNSCC.

Begum S, Brait MR, Califano JA, Carvalho AL, Chuang A, Fazio VM, Henrique R, Jerónimo C, Jiang WW, Koch W, Lee J, Liu C, Moon CS, Nayak CS, Park HL, Poeta L, Ratovitski E, Sidransky D, Trink B, Westra W, Zhao M, Zhou S

17018594

Cancer Res., 2006, 66 (19)