Microsatellite Instability and Mutations in DNA Mismatch Repair Genes in Sporadic Colorectal Cancers |
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Authors: | Jeong Seung-Yong |
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Institution: | (1) Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea, Laboratory of Cell Biology, Cancer Research Center and Cancer Research Institute, and Department of Pathology, Seoul National University College of Medicine, Seoul, Korea |
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Abstract: | PURPOSE: This study was designed to investigate the frequency
of mutations in DNA mismatch repair genes in
sporadic colorectal cancers. METHODS: Genomic DNAs
procured from paraffin blocks of the pathologic specimens
from 230 consecutive patients with colorectal cancer were
examined for their microsatellite instability status using a
mononucleotide microsatellite marker, BAT-26, and also
evaluated expressions of hMLH1, hMSH2, and hMSH6 proteins
by immunohistochemical staining. Any of these 230
patients did not have family histories of hereditary nonpolyposis
colorectal cancer, familial adenomatous polyposis,
colorectal cancer, or hereditary nonpolyposis colorectalrelated
cancers, such as endometrial, small bowel, and ureteral
and renal pelvic cancers. When microsatellite instability
was positive, mutations in the simple repeated
sequences of TGF-RII, BAX, IGF IIR, hMSH3, and hMSH6
genes were examined. In microsatellite instability–positive
or staining-negative cases, polymerase chain reaction–single-
strand conformation polymorphism and DNA sequencing
detected mutations of hMLH1, hMSH2, and hMSH6
genes. If mutations were found in tumor tissue samples, we
tested for a germline mutation with a microdissected corresponding
normal tissue. RESULTS: Among 230 cases of
sporadic colorectal cancer, 21 (9.1 percent) manifested
microsatellite instability. In the immunohistochemical staining,
20 (8.6 percent) showed loss of expressions. All 20
staining-negative cases were microsatellite instability–positive.
Only 1 of 21 (4.8 percent) microsatellite instability–
positive cases showed intact staining for three proteins. The
frame-shift mutations of the simple repetitive sequences
were found in 17 cases (81.0 percent) in TGF-RII, 11 (52.4
percent) in BAX, 5 (23.8 percent) in IGF IIR, 7 (33.3 percent)
in hMSH3, and 8 (38.1 percent) in hMSH6 genes.
Germline mutation was observed in only one case, which
accounts for 4.8 percent among positive microsatellite instability
and 0.4 percent of total patients, and was found in
hMSH2. Five somatic mutations (2 in hMLH1, 2 in hMSH2,
and 1 in hMSH6) also were found. CONCLUSION: The
results indicated that a germline mutation of DNA mismatch
repair gene was a rare event in sporadic colorectal cancers. |
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Keywords: | |
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