Molecular changes of colorectal cancer in Singapore.
Improved success in the management of colorectal cancer requires a better understanding of its development and biological behaviour. The key for this is molecular genetics. Gene changes parallel the multi-step changes in the adenoma-carcinoma sequence. Cancer results from a variable combination of defects in oncogenes, tumour suppressor, mutator and apoptotic genes. These changes are similar whether they occur in inherited disorders like adenomatous polyposis coli (APC) and hereditary non-polyposis colorectal cancer (HNPCC) or acquired cancer in the elderly. In Singapore, the c-myc and c-Ki-ras proto-oncogenes are found to be activated in 70% and 29% of tumours respectively. Allelic loss of chromosome 5q and 17p occurs in 25% and 70% of tumours respectively, while point mutation of the p53 tumour suppressor gene occurs in 50% of colorectal cancers. Both the frequency and the nature of the lesion occurring are compatible to the changes detected in Caucasian patients, suggesting common aetiological factors. The biological behaviour of colorectal adenocarcinomas is determined by the nature of defects or mutations in key genes such as the p53 tumour suppressor gene. Lymphatic spread is associated with the presence of point mutations and haematogenous spread is associated with loss of heterozygosity of p53. Survival is worse when conserved regions of the gene are mutated compared with those outside, and worst when codon 175 is mutated. Sensitivity to radiotherapy and chemotherapy is also determined by p53 mutation which controls apoptosis. Prognosis could now be individualised and with the prospect of gene therapy, molecular genetics will have a major impact on the management of colorectal cancer.
Goh
H S
HS
Gleneagles Medical Centre, Singapore.
Khine
K
K
Elnatan
J
J
Yao
J
J
Smith
D R
DR
D000230:Adenocarcinoma / Q000208:ethnology* / Q000235:genetics* / Q000503:physiopathology; D044466:Asian People / Q000235:genetics; D015179:Colorectal Neoplasms / Q000208:ethnology* / Q000235:genetics* / Q000503:physiopathology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D008967:Molecular Biology; D009154:Mutation; D011519:Proto-Oncogenes / Q000502:physiology; D012846:Singapore / Q000453:epidemiology