Polymorphism in the thymidylate synthase promoter enhancer region is not an efficacious marker for tumor sensitivity to 5-fluorouracil-based oral adjuvant chemotherapy in colorectal cancer.

Thymidylate synthase (TS) is the target enzyme of 5-fluoropyrimidines. The TS gene promoter enhancer region (TSER) possesses tandem, repeated, regulatory sequences that are polymorphic in humans. This polymorphism has been reported to influence TS expression in vitro and in vivo. In this study, we assessed whether or not the TSER genotype is an efficacious marker for tumor sensitivity to 5-fluorouracil (5-FU)-based oral adjuvant chemotherapy for colorectal cancer. One hundred and thirty-five Japanese patients who received curative resection and 5-FU-based oral adjuvant chemotherapy were studied. TSER genotypes of the tumors were analyzed by PCR. The numbers of repeated sequences of representative bands were determined by direct sequence. The genotypes of two-/two-repeats (TSER 2/2), two-/three-repeats (TSER 2/3), three-/three-repeats (TSER 3/3), and three-/five-repeats (TSER 3/5) were found in 11 (8.1%), 32 (23.7%), 85 (63.0%), and 7 (5.2%) tumors, respectively. Patients were classified into two groups: TSER 2/2 or 2/3 group; and the TSER 3/3 group. The relationship between the TSER genotype group and disease-free intervals was analyzed by univariate and multivariate analyses. Five-year disease-free survivals of the TSER 2/2 or 2/3 group and the TSER 3/3 group were 77% and 75%, respectively (P = 0.89). Multivariate analysis revealed that stage was the only independent prognostic factor and that the TSER genotype did not have a prognostic significance (hazard ratio for TSER 3/3, 0.91; P = 0.84). In conclusion, TSER genotype is not an efficacious marker for tumor sensitivity to 5-FU-based oral adjuvant chemotherapy for Japanese colorectal cancer patients after curative resection.

Frequent gains of 20q and losses of 18q are associated with lymph node metastasis in intestinal-type gastric cancer.

BACKGROUND: The genetic aberrations associated with development and progression of gastric carcinomas (GCs) are poorly understood. The aim of this study was to identify chromosomal aberrations associated with the development and/or progression of intestinal-type GC. MATERIALS AND METHODS: Comparative genomic hybridization (CGH) analysis was applied to 36 intestinal-type GCs. We compared chromosomal aberrations detected by CGH analysis with clinicopathological parameters. RESULTS: Frequent gains of DNA copy number were found on 8q, 13q, 20q, 3q, 6q and losses were found on 17p, 18q in intestinal-type GCs. No significant differences were observed in the chromosomal aberrations between tumor stage, tumor location, peritoneal dissemination, liver metastasis or other distant metastasis. However, the frequencies of 20q12-13 gain and 18q21-22 loss were significantly higher in tumors with lymph node metastasis than in those without metastasis. CONCLUSION: Gains of 20q and losses of 18q may contribute to lymph node metastasis and the malignant phenotype in intestinal-type GCs.

Numerical aberrations of chromosome 17 and the p53 locus in small hepatocellular carcinomas.

To investigate numerical aberrations of chromosome 17 and the p53 locus in early stages of hepatocellular carcinoma (HCC), 12 fresh-frozen specimens of small HCCs (less than 30 mm in size) were examined by dual-color fluorescence in situ hybridization. We used a chromosome 17 alpha-satellite DNA probe and a p53 locus-specific DNA probe. We also performed immunohistochemical analysis for p53 protein in the same cases. Gain of chromosome 17 was the most frequently observed anomaly, present in 58% of cases, and deletion of the p53 locus was observed in 50% of cases. The combination of chromosome 17 gain and p53 locus deletion was observed in 33.3% of cases. However, overexpression of p53 protein was not observed in any specimens. Our results suggest that gain of chromosome 17 and deletion of the p53 locus could represent early genetic events, prior to overexpression of p53 protein due to mutation, in early stage HCC.

[A case of liver metastasis of colon cancer responding remarkably to 5'-DFUR].

A 65-year-old man was referred to our hospital because of diarrhea due to sigmoid colon cancer. Abdominal CT scan revealed a hepatic tumor (S8) about 2 cm in diameter. We performed a sigmoidectomy and planned to resect the liver metastasis 1 or 2 months later. Pathological findings showed moderately differentiated adenocarcinoma, s, n1. Two weeks after the surgery, 5'-DFUR was administered at 600 mg/day. An abdominal CT scan 2 months later demonstrated regression of the liver metastasis and another scan 4 months later showed the tumor had disappeared. 5'-DFUR was administered for about 2 years. Five years after the surgery, the patient is alive without recurrence and CEA level is in normal range.

Detection of p53 gene mutations by nonisotopic RNase cleavage assay as a predictor of poor prognosis in colorectal cancers.

The present study was undertaken to evaluate p53 gene mutation as a prognostic factor in patients with colorectal cancer. Nonisotopic RNase cleavage assay (NIRCA), recently used for detecting gene mutations, was employed to detect p53 gene mutations in this study. In 15 samples of colorectal tumors, NIRCA was confirmed to be simple, accurate, and thus useful for clinical use, compared with polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP). In another group of 79 cases of colorectal cancer analyzed for p53 gene mutation by using NIRCA, mutations were detected in 58 of 79 (73.4%) cases. Multivariate Cox proportional-hazards analysis showed that p53 gene mutation was a significant prognostic factor in patients with colorectal cancer. Our results showed that NIRCA is a simple and sensitive method, and thus useful for genetic screening of colorectal cancer. Furthermore, our results showed that p53 gene mutation is an independent predictor of poor prognosis in colorectal cancers.