Loss of Dpc4 expression in colonic adenocarcinomas correlates with the presence of metastatic disease.

DPC4 is a candidate tumor suppressor gene on chromosome 18q21, a region that shows high frequencies of allelic losses in pancreatic and colorectal adenocarcinomas. Biallelic inactivation of DPC4 has been reported in half of pancreatic cancers, but are relatively infrequent in other tumor types. The role of DPC4 inactivation in colorectal neoplasms has not been fully characterized. An immunohistochemical assay for Dpc4 protein expression has been recently developed and shown to be a sensitive and specific surrogate for alterations in the DPC4 gene. In this study we examined the expression of Dpc4 protein in formalin-fixed archival tissue from 83 colorectal lesions, including 19 adenomas and 64 sporadic adenocarcinomas (11 stage I, 13 stage II, 17 stage III, and 23 stage IV cancers). None of the adenomas or stage I adenocarcinomas showed loss of Dpc4 expression, whereas one of 13 (8%) stage II, one of 17 (6%) stage III, and five of 23 (22%) of stage IV cancers showed loss of Dpc4 expression. There was a borderline significant difference in loss of Dpc4 reactivity in colorectal tumors with distant metastasis at presentation (22%) versus primary tumors without distant metastasis (5%) (Fisher's exact test, P = 0.05; chi(2) = 0.04). Poorly differentiated histology or status of pericolonic lymph nodes did not affect Dpc4 expression. Alterations in DPC4 are involved in the progression of a subset of colorectal carcinomas, especially those that present with advanced disease. In the sequential pathogenesis of colorectal tumors, inactivation of DPC4 is likely to be a late event.