- 期刊
- OpenAccess
Two-hit Hypothesis of Tumor Suppressor Gene and Revisions
並列摘要
Knudson proposed his now famous two-hit hypothesis to explain mechanisms involved in inactivating tumor suppressor genes during tumorigenesis. Knudson suggested that two genetic events (hits) are required to abolish both alleles of a tumor suppressor gene, and, more importantly, both familial and sporadic forms of the same cancer are caused by mutations of the same tumor suppressor gene. Genomic loss is always the most common “hit” that inactivates a tumor suppressor gene. This is reflected in a genetic mechanism called loss of heterozygosity (LOH). As a result, the detection of recurrent LOH in a chromosomal region is now considered to be critical evidence for the localization of tumor suppressor genes. However, in sporadic cancers, with a few exceptions, the probability of fining somatic mutation in certain tumor suppressor genes with a high frequency of LOH has been shown to be extremely rare. Recent evidence has suggested two non-mutually exclusive possibilities provided support for a tumorigenic role for these genes defined solely by LOH. The first possibility is that a growing number of common tumor suppressor genes have been found to exhibit the haplo-insufficiency phenotype, which implies that homozygous inactivating mutations and complete loss of function are not necessary to cause defective tumor suppressor function. The second possibility is that other (epigenetic) inactivation mechanisms abrogating the function of these genes are implicated in tumorigenesis. For example, hyper-methylation of the promoter region has been found in some tumor suppressor genes. Based on a study seeking for two hits on E-Cadherine, a tumor suppressor gene associated with tumor metastasis, we suggest that maintaining a reversible mechanism, either by controlling the gene at the transcriptional level or by retaining an intact allele subsequent to LOH, might be important for tumor suppressor genes possessing diverse functions. Thus, inactivation of both alleles of a tumor suppressor gene might not be totally beneficial for tumor development.