The importance of p53 inactivation in colorectal cancer among Hong Kong Chinese was investigated by screening directly for p53 mutations by DNA sequencing techniques and by using a yeast functional assay to detect mutations in the gene which affect its ability for transcriptional transactivation. The purpose of this study was to evaluate the contribution of p53 inactivation to colorectal cancer development and to define and localize the mutations to compare them with the p53 mutation spectrum among Caucasians. If specific environmental and dietary carcinogens are involved in the genesis of colorectal cancer among the Chinese patients, then this approach was expected to reveal differences in hot spots for mutation....[ Read more ]

The importance of p53 inactivation in colorectal cancer among Hong Kong Chinese was investigated by screening directly for p53 mutations by DNA sequencing techniques and by using a yeast functional assay to detect mutations in the gene which affect its ability for transcriptional transactivation. The purpose of this study was to evaluate the contribution of p53 inactivation to colorectal cancer development and to define and localize the mutations to compare them with the p53 mutation spectrum among Caucasians. If specific environmental and dietary carcinogens are involved in the genesis of colorectal cancer among the Chinese patients, then this approach was expected to reveal differences in hot spots for mutation.

Alterations in the p53 tumor suppressor gene are the most commonly detected genetic changes in human cancers. In this study ninety-nine colorectal carcinomas from Hong Kong patients were analyzed for mutations in p53 gene by single-strand conformation polymorphism (PCR-SSCP) analysis and direct DNA sequencing. Thirty-five of the 99 tumors (35.4%) contained mutations. These studies showed both similarities and differences in mutations detected in Chinese versus Caucasians. Point mutations accounted for 80% of all genetic changes and were predominantly base transitions at CpG dinucleotide sites, a predominant feature also common to Caucasian carcinomas. A mutational spectrum for exons 5-8 of the p53 tumor suppressor gene in colorectal carcinomas in Hong Kong Chinese was established. When compared with the p53 mutations detected from Caucasian studies, the major hot spots at codons 175 and 248 are also hot spots in the Chinese. However, the hot spot at codon 273 in the Caucasian population is not mutated at a high frequency in the Chinese population. Moreover, a significantly higher frequency (20%) of deletion and insertion mutations was observed in Hong Kong colorectal cancer patients. Distinct genetic and/or environmental factors may contribute to these findings.

The p53 yeast functional assay provides an alternative screening method for p53 inactivating mutations. In this study two groups of colorectal cancer specimens were studied, those which were negative for p53 mutations screened by the PCR-SSCP technique and those which had known mutations localized by DNA seqiencing. The p53 yeast functional assay identified 9 (45%) out of the 20 SSCP-negative tumor samples harbored mutant p53. Thus, the mutation frequency of 35.4% for the p53 tumor suppressor gene in Hong Kong colorectal cancer patients is underestimated by the PCR-SSCP method alone. Furthermore, this functional assay provides evidence that the mutations detected by the PCR-SSCP technique, are indeed functionally inactivating mutations, which are expected to contribute to loss of cell growth control and eventual tumorigenesis.