Basic Research
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 14, 2005; 11(6): 778-784
Published online Feb 14, 2005. doi: 10.3748/wjg.v11.i6.778
Loss of heterozygosity: An independent prognostic factor of colorectal cancer
Shih-Ching Chang, Jen-Kou Lin, Tzu-Chen Lin, Wen-Yih Liang
Shih-Ching Chang, Jen-Kou Lin, Tzu-Chen Lin, Division of Colon and Rectal Surgery, Department of Surgery, Veterans General Hospital-Taipei, National Yang-Ming University, Taiwan, China
Wen-Yih Liang, Department of Pathology, Veterans General Hospital-Taipei, National Yang-Ming University, Taiwan, China
Shih-Ching Chang, Institute of Clinical Medicine, National Yang-Ming University, Taiwan, China
Author contributions: All authors contributed equally to the work.
Supported by grants from the Veterans General Hospital-Taipei, VGH90348 and VGH910305
Correspondence to: Jen-Kou Lin, M.D., Ph.D., Division of Colon and Rectal Surgery, Department of Surgery, Veterans General Hospital-Taipei, No. 201, Sec. 2, Shih-Pai Rd, 11217 Taipei, Taiwan, China. jklin@vghtpe.gov.tw
Telephone: +886-2-28757544-110 Fax: +886-2-28757639
Received: April 4, 2004
Revised: April 6, 2004
Accepted: May 13, 2004
Published online: February 14, 2005
Abstract

AIM: Colorectal cancers result from the accumulation of several distinct genetic alterations. This study was to investigate the frequency and prognostic value of loss of heterozygosity (LOH) and microsatellite instability (MSI) at 14 genetic loci located near or within regions containing important genes implicated in colorectal tumorigenesis.

METHODS: We studied colorectal cancers with corresponding normal mucosae in 207 patients (139 males and 68 females, mean age at the time of tumor resection 66.2±12.4 years, range 22-88 years). There were 37 right-sided colonic tumors, 85 left-sided colonic tumors and 85 rectal tumors. The distribution of tumor staging was stage I in 25, stage II in 73, stage III in 68, and stage IV in 41. We analyzed the LOH and MSI of HPC1, hMSH2, hMLH1, APC, MET, P53, NH23-H1, DCC, BAT25, BAT26, D17S250, MYCL1 and D8S254 with fluorescent polymerase chain reaction and denatured gel electrophoresis. High-frequency LOH was determined to be greater than three, or more than 50% of the informative marker with LOH. High-frequency MSI (MSI-H) was determined as more than four markers with instability (>30%). Correlations of LOH and MSI with clinical outcomes and pathological features were analyzed and compared.

RESULTS: The occurrence of MSI-H was 7.25%, located predominantly in the right colons (7/15) and had a higher frequency of poor differentiation (6/15) and mucin production (7/15). LOH in at least one genetic locus occurred in 78.7% of the tumors and was significantly associated with disease progression. Of the 166 potentially cured patients, 45 developed tumor recurrence within 36 mo of follow-up. Clinicopathological factors affecting 3-year disease-free survival (DFS) were TNM staging, grade of differentiation, preoperative CEA level, and high LOH status. Patients with high LOH tumors had a significantly lower DFS (50%) compared with patients with low LOH tumors (84%). Of the patients developing subsequent tumor recurrence, the number and percentage of LOH were 2.97 and 46.8% respectively, similar to the stage IV disease patients. TNM staging had the most significant impact on DFS, followed by high LOH status.

CONCLUSION: Clinical manifestations of LOH and MSI are different in colorectal cancer patients. High-frequency LOH is associated with high metastatic potential of colorectal cancers.

Keywords: Colorectal Cancer; Loss of Heterozygosity; Prognosis