Clinicopathological Correlation of hMLH1 and hMSH2 Protein Expressions in Stage III Colon Cancer

PURPOSE: Functional loss of mismatch repair has been reported to be the reason for resistance to several chemotherapeutic drugs. The expressions of hMLH1 and hMSH2 were examined to assess whether they correlated with the biological behavior and the chemotherapeutic responsiveness in paflents with sporadic colon cancers. METHODS: Ninety-one patients with stage III primary colon cancer were included from the tumor registry of the Asan Medical Center, Seoul, Korea. All patients underwent a curative operation and postoperative chemotherapy with 5- fluorouracil and leucovorin for 6 cycles between 1993 and 1997. Immunohistochemical staining for hMLH1 and hMSH2 was performed using archival paraffin blocks. A positive expression was determined when unequivocal nuclear staining was identified in more than 10% of the cancer cells. The survival and the clinicopathologic variables regarding hMLH1 and hMSH2 expressions were assessed using the log-rank test and the Cox proportional regression method. RESULTS: Either hMLH1 or hMSH2 expression was lost in nine cases (9.9%). hMLH1 and hMSH2 expressions were significantly correlated with tumor invasion (P=0.012) and tumor differentiation (P=0.017). The disease-free survival did not differ with respect to hMLH1 and hMSH2 expressions. The number of metastatic lymph nodes and the preoperative serum CEA level were independent predictors of disease-free survival on a multivariate analysis. CONCLUSIONS: The loss of hMLH1 or hMSH2 expresscon appears to be involved in the differentiation of and the invasion by colon cancer. However, nether hMLH1 nor hMSH2 expression was correlated withthe 5-fluorouracil responsiveness.

Characterization of Mutator Pathway in Younger-age-onset Colorectal Adenocarcinomas

The high-frequency microsatellite instability (MSI-H) phenotype, frequently identified in hereditary nonpolyposis colorectal cancer (HNPCC), also accounts for approximately 15% of sporadic colorectal cancers. Microsatellite instability (MSI) occurs from the mutational inactivation of the DNA mismatch repair genes, i.e. hMSH2 and hMLH1 in HNPCC, as well as from epigenetic inactivation of hMLH1 in sporadic colorectal tumors. The mutator pathway including microsatellite instability, hMLH1 promoter methylation, and hMSH2 and hMLH1 mutation patterns were identified in 21 sporadic colorectal adenocarcinoma patients younger than 30 yr excluding HNPCC. More than half of tumors showed MSI, with five MSI-H and six MSI-L (low-frequency microsatellite instability). Three of six MSI-H tumors showed the hMLH1 promoter methylation and did not express the hMLH1 protein. On the other hand, all MSI-L and all MSS (microsatellite stable) tumors expressed both hMSH2 and hMLH1 proteins. Two novel mutations, i.e. a missense mutation in hMLH1 and a splice-site alteration in hMSH2, were identified in two patients respectively. Although mutator pathway was implicated in younger-age-onset colorectal carcinogenesis, many tumors appeared to evolve from different genetic events other than hMSH2 and hMLH1 mutations frequently identified in HNPCC.

Meckel-Gruber syndrome

Meckel-Gruber syndrome is a multiple malformation syndrome featuring occipital meningoencephalocele, multicystic dysplasia of kidney, cystic and fibrotic change of liver, polydactyly, and other characteristics inherited by the autosomal recessive trait. We exprienced a case of Meckel-Gruber syndrome in a newborn male diagnosed clinically and confirmed pathologically. Abnormalities of the fetus were found prenataly by ultrasonogram, and subsequently the baby was terminated by cesarean section delivery at 32 weeks of gestational age. We report this case with brief review of literature.