Clinicopathologic and carcinogenetic appraisal of DNA replication error in sporadic T3N0M0 stage colorectal cancer after curative resection

Abstract

BACKGROUND/AIMS: DNA replication error (RER) was found to play a role in the carcinogenesis of a subset of sporadic colorectal cancers. This study was conducted to evaluate the clinicopathologic implications of RER in T3N0M0 stage colorectal cancers. To better understand the carcinogenesis of sporadic colorectal cancer, the RER status was further correlated with the alterations of K-ras, p53 and deleted in colorectal cancer (DCC) genes which were frequently involved in the adenoma-carcinoma sequence. METHODOLOGY: Seventy-eight patients with curatively resected T3N0M0 stage sporadic colorectal cancer were accumulated. The stored frozen tissues were retrieved for analyses of 1) microsatellite instability at 7 distinct chromosomal loci, 2) loss of heterozygosity at DCC gene, 3) K-ras gene mutation, 4) p53 expression, and 5) DNA content. The RER status was correlated with various clinicopathologic and molecular genetic factors. The survival of patients stratified by RER status was analyzed by Kaplan-Meier estimator. RESULTS: The PER-positive tumor was detected in 32.1% (25/78) of patients. The RER-positive cancer patients presented with distinct clinicopathologic features including young age of tumor onset, proximal tumor location, mucin production in histology, a higher rate of synchronous and metachronous colorectal cancers, and an increased incidence of extracolonic primary cancer. Patients with RER-positive tumor were found to have an improved prognosis with the 5-year survival probability of 76% and 45% in REP-positive and RER-negative groups, respectively (p < 0.05). The RER-positive tumors tended to have normal p53 expression, DNA diploidy, and a lower DNA index. The rate for the loss of heterozygosity of DCC gene was significantly lower in REP-positive tumors. RER status was not associated with K-ras mutation. CONCLUSIONS: The clinicopathologic features and carcinogenesis of RER-positive sporadic colorectal cancers were considered different from those of REP-negative tumors. The presence of RER may identify a subset of less aggressive tumors with good prognosis in T3N0M0 stage colorectal cancers.