산발성 대장암에서 17p13과 18q21의 현미부수체 불안정성과 이형접합자 소실의 의의
Significance of microsatellite instability and loss of heterozygosity on 17p13 and 18q21 of sporadic colorectal cancer
산발성 대장암 17p13 18q21 현미부수체;
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Purpose: Generally colorectal cancer can progress through two pathways of genomic instability: chromosomal and microsatellite instability. The loss of heterozygosity(LOH) is known to be related with the allelic loss of various tumor suppressor genes, and microsatellite instability(MSI) which results from defective mismatch repair(MMR) mechanisms. MSI has been implicated in the etiology of hereditary nonpolyposis colorectal cancer(HNPCC) and some portion of sporadic colorectal cancers. However, the underlying mechanisms of the MSI are different from hereditary colorectal cancers and sporadic colorectal cancers. In this study, the status of LOH of 17p13 and 18q21, which located p53 and SMAD4, and MSI were examined simultaneously in sporadic colorectal cancers, and their correlation with clinical parameters investigated. And the relation between MSI and LOH was analyzed. Methods: One hundred patients who were diagnosed as colorectal cancer and consequently operated at Department of Surgery, Korea University, College of Medicine from Jan. 1995 to Dec. 1998 were enrolled this study. The author obtained tumoral and normal DNA from formalin-fixed paraffin-embedded archival tissue with microdissection technique and through polymerase chain reaction(PCR) and analyzed for the presence of MSI and LOH. MSI was examined with microsatellite markers of BAT25, BAT26, D2S123, D5S346 and D17S250 as recommended in the 1997 National Cancer Institute International Workshop on Microsatellite Instabilities. The LOH of 17p13 was examined with D17S796, TP53, D17S5, D17S513, and in case of 18q21, D18S1156, D18S363, D18S21, D18S34, D18S58 were used as primer. To identify the protein expression of p53 and SMAD4, immunohistochemical staining using relevant monoclonal antibody was performed. Results: MSI was detected in 23 cases(23%), and MSI-H was 18%. Sex of patients, tumor location, differentiation of tumor were not related to MSI, but in patients with less invasive tumor, non lymph-node metastasis, and early stage cancer, MSI was more frequently detected. The 5-year survival rates was better in patients with MSI statistically(86.7% vs. 59.9%, P=0.025). LOH was detected in 78 cases(78%), LOH of 17p13 and 18q21 was 51% and 64% respectively. Contrary to MSI, LOH was more frequently detected in patients with lymph-node metastasis. Although there was no significant difference in 5-year survival rates, but it was poor than in patients without LOH(61.6% vs. 81.1%, P=0.078). The overlap between LOH and MSI was only 6.4%, in particular, overlap between LOH and MSI-H was 2.6%. The positive expression of p53 and SMAD4 by immunohistochemical staining was detected 58% and 32% respectively. They were not related to clinical and pathological parameters. Only 47.1%(p53) and 32.8%(SMAD4) of patients with each LOH were positive for immunohistochemical staining. Conclusions: These results suggest that MSI is partially involved in sporadic colorectal carcinogenesis and showing better survival. On the contrary, the tumors with LOH of 17p13 and 18q21 have more aggressive clinicopathologic natures than tumor with MSI. These two pathways are thought to be involved independently to carcinogenesis of sporadic colorectal cancer.