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 tha t shows high frequencies of allelic losses in pancreatic and colorectal ade nocarcinomas, Biallelic inactivation of DPC4 has been reported in half of p ancreatic cancers, but are relatively infrequent in other tumor types. The role of DPC4 inactivation in colorectal neoplasms has not been fully charac terized. An immunohistochemical assay for Dpc4 protein expression has been recently developed and shown to be a sensitive and specific surrogate for a lterations in the DPC4 gene. In this study we examined the expression of Dp c4 protein in formalin-fixed archival tissue from 83 colorectal lesions, in cluding 19 adenomas and 64 sporadic adenocarcinomas (11 stage I, 13 stage Z I, 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%) stag e Ii, one of 17 (6%) stage III, and five of 23 (22%) of stage IV cancers sh owed 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 histol ogy or status of pericolonic lymph nodes did not affect Dpc4 expression. Al terations in DPC4 are involved in the progression of st subset of colorecta l carcinomas, especially those that present with advanced disease. In the s equential pathogenesis of colorectal tumors, inactivation of DPC4 is likely to be a late event.