Three types of genes contribute to CRC tumorigenesis. These include oncogenes. TSGs, and MMR genes. This study aims to reveal the significance of oncogenes, TSGs and the genomic instability in Hong Kong Chinese CRC patients. The frequencies of genetic alterations in Hong Kong Chinese CRC were compared to those in Caucasians and Japanese. The significance of the Ki-ras oncogene was evaluated by screening Ki-ras codon 12 point activational mutations by PCR-ASO hybridization while that of TSGs was investigated by PCR-LOH analysis. For the importance of genomic instability in Hong Kong sporadic CRC, the RER status indicator, BAT-26, was used. Specific biomarkers may have independent prognostic significance. Another aim of this study was examination of the association between clinical and pa...[ Read more ]

Three types of genes contribute to CRC tumorigenesis. These include oncogenes. TSGs, and MMR genes. This study aims to reveal the significance of oncogenes, TSGs and the genomic instability in Hong Kong Chinese CRC patients. The frequencies of genetic alterations in Hong Kong Chinese CRC were compared to those in Caucasians and Japanese. The significance of the Ki-ras oncogene was evaluated by screening Ki-ras codon 12 point activational mutations by PCR-ASO hybridization while that of TSGs was investigated by PCR-LOH analysis. For the importance of genomic instability in Hong Kong sporadic CRC, the RER status indicator, BAT-26, was used. Specific biomarkers may have independent prognostic significance. Another aim of this study was examination of the association between clinical and pathological parameters and individual molecular markers (Apt, Mcc, and Dcc TSGs, Ki-ras oncogene and RER phenotype).

This study included 99 colorectal carcinomas and their matching normal tissues. Thirty of the 99 (30%) specimens showed Ki-ras codon 12 mutations. Aspartic acid1 substitutions were the most frequent mutation among the five specific types of mutatiom detected. The frequency of Ki-ras codon 12 mutations in Chinese was similar to previous studies in Caucasians and Japanese. For the patterns of Ki-ras codon 12 mutations, Hong, Kong CRC patients had a remarkably similar one to that observed in the US and Japan, while the pattern differed significantly from that observed in Western Europe. A significantly lower incidence of aspartic acid substitutions and G-to-A transitions at Ki.ras codon 12 were observed in Western European CRC patients, while these were the predominant changes in Hong Kong Chinese CRC patients. The results suggested that the etiologic cause of Ki-ras codon 12 mutations in CRC patients with different ethnic origins may vary geographically. The TSGs are the second category of genes involved in the CRC model. The frequencies of allelic losses of Apc, Mcc and Dcc were 31.3% (15/48), 11.6% (5/43), and 44.4% (20/45), respectively, for Hong Kong Chinese CRC patients. The frequency of Apc LOH was similar, the Mcc LOH was lower, and the Dcc LOH was higher than previous Caucasian and Japanese reports. In Hong Kong Chinese CRC, the RER+ phenotype occurred at a frequency of 10% (10/99). This frequency was similar to other studies using microsatellite markers where RER+ frequencies ranged from 11% to 28%. The rates of genetic alterations in RER+ tumors were lower in p53, Mcc and Dcc; similar in Apc; and higher in Ki-ras as compared to that observed in RER-tumors. None of these differences achieved statistical significance, however. L-myc genotyping was done in the same group of patients. The ratio of S to L alleles in the current study population was 0.51:0.49. There were 26.3% (26/99) CRC patients harboring the SS genotype, 46.5% (46/99) the LS genotype, and 27.3% (27/99) the LL genotype. Allele and genotype frequencies for the L-myc gene in Hong Kong CRC were similar to Caucasian and Japanese groups.

The usefulness of individual molecular markers including Apc, Mcc and Dcc, LOH, Ki-ras codon 12 point mutations, and the RER phenotype for independent prognosis of Hong Kong Chinese CRC patients was assessed. None of the biomarkers examined were predictive of the survival independently. However, the Ki-ras mutations were associated significantly with well-differentiated tumors and the RER+ phenotype was correlated significantly to the less aggressive Dukes' stage B. Tumors with Ki-ras codon 12 point activational mutations and RER+ phenotypes are positively correlated with the degree of differentiation and Dukes' staging, respectively, and an improved prognosis. Previous studies showed the presence of 18q allelic loss and L-myc SS genotype were associated with a poorer prognosis. The L-myc SS genotype was associated with the Dukes' stage C in this current study. No evidence supported the association of the L-myc SS genotypes with Dcc LOH and poor prognosis. RER+ phenotypes are associated significantly with poorly differentiated tumors in this current study. Additionally, this study supported the observation that a subset of younger male CRC patients in Hong Kong developed CRC by the RER pathway. The RER+ phenotype associated significantly with male CRC patients and with those aged below 50 years. Multiple genetic alterations occur commonly in CRC. Twenty-nine tumors harbored more than one alteration; 20 had two alterations; 6 had three alterations, and 3 had four alterations in this study of Hong Kong Chinese CRC patients. There was no evidence to support the use of multiple genetic alterations as a prognostic panel of biomarkers for Hong Kong CRC patients.