Hiroyuki Yakushiji

Deficient expression ofO 6-Methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma

BackgroundO6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that transfers methyl groups fromO6-methylguanine to itself. Alkylation of DNA at theO6 position of guanine is an important step in the induction of mutations in the organism by alkylating agents. TheO6-methyl G:T mismatch is recognized by the mismatch-repair (MMR) pathway. The biliary duct is highly exposed to alkylating agents because of its anatomical location.MethodsWe examined 39 surgically resected gallbladder carcinomas and 35 extrahepatic bile duct carcinomas and evaluated the expression of MGMT and MMR protein (hMLH1 and hMSH2) by immunohistochemical staining.ResultsMGMT-negative staining was detected in 59.0% of gallbladder carcinoma specimens and 60.0% of extrahepatic bile duct carcinoma specimens. In gallbladder carcinoma, hMLH1- and hMSH2-negative staining was observed in 51.3% and 59.0%, respectively, whereas in extrahepatic bile duct carcinoma, the respective values were 57.1% and 65.7%. MGMT-negative staining correlated with hepatic invasion in gallbladder carcinoma and with poor prognosis in both types of tumor. Furthermore, a combined MGMT and MMR status was shown to be a more significant prognostic biomarker in both tumor types.ConclusionsCombined MGMT and MMR is a possible prognostic marker that probably reflects an accumulation of genetic mutations.

Expression and Prognostic Significance ofO6-Methylguanine-DNA Methyltransferase in Hepatocellular, Gastric, and Breast Cancers

AbstractBackground:O6-Methylguanine-DNA methyltransferase MGMT is an enzyme that repairs O6-methylguanine, a promutagenic DNA base damaged by endogenous and environmental alkylating agents. There are few reports that describe whether or not abnormal MGMT expression correlates with the prognosis in human solid cancers. Methods: The expression of MGMT was immunohistochemically evaluated in 60, 62, 105, and 46 paraffin-embedded samples from patients with curatively resected hepatocellular, gastric, colorectal, and breast cancers, respectively. Results: The expression of MGMT was a positive predictive factor for overall survival in hepatocellular P = .005 and gastric cancers P < .001 and for relapse-free survival in breast cancers P < .001. MGMT-positive gastric tumors n = 42 were correlated with the absence of serosal invasion P = .045, lymph node metastasis P = .006, intestinal type P = .018, and low pathological tumor, node, metastasis stage P < .001. All breast tumors that recurred locally after operation were MGMT negative P = .004. The clinicopathologic characteristics of colorectal cancers with respect to MGMT expression did not significantly differ. Conclusions: The expression of MGMT is a predictive prognostic marker in patients with hepatocellular, gastric, and breast cancers. These findings may help to establish therapeutic strategies for patients with these types of solid cancer.

DNA mismatch repair deficiency in curatively resected sextuple primary cancers in different organs: a molecular case report

A male patient synchronously or metachronously underwent six curative resections after diagnoses of cancers in the rectum, urinary bladder, stomach, colon, liver and lung. Five cancers, excluding early colon cancer, were analyzed for instability in seven microsatellite markers and in transforming growth factor beta type II receptor, insulin-like growth factor II receptor and BAX. All analyzed cancers had replication errors and instability in at least one target gene. These results suggest that abnormal DNA mismatch repair system plays a major role in the occurrence of multiple primary cancers in this case.