10 Unlike the majority of tumor suppressor genes, such as RB, APC, or BRCA1, which are usually inactivated during cancer progression by deletions or truncating mutations, the TP53 gene in human tumors is often found to undergo missense mutations, in which a single nucleotide is substituted by another. 9 The importance of p53 as a cardinal player in protecting against cancer development is further emphasized by Li-Fraumeni syndrome (LFS), a rare type of cancer predisposition syndrome associated with germline TP53 mutations. For further information, see the IARC TP53 mutation database version R15, November 2010. 6 Indeed, TP53 mutations were reported to occur in almost every type of cancer at rates varying between 10% (e.g., in hematopoietic malignancies 7) and close to 100% (e.g., in high-grade serous carcinoma of the ovary 8). 4, 5 The many roles of p53 as a tumor suppressor include the ability to induce cell cycle arrest, DNA repair, senescence, and apoptosis, to name only a few. This model was later expanded to include additional genetic aberrations, such as inactivation of a tumor suppressor and activation of an oncogene, as hits.ĭespite the huge diversity in the genes implicated in tumorigenesis, the p53 transcription factor (encoded by the human gene TP53) stands out as a key tumor suppressor and a master regulator of various signaling pathways involved in this process.
2 More than 2 decades later, Knudson proposed a theory for tumor development known as the “Knudson two hit hypothesis.” 3 This theory suggested a genetic model for retinoblastoma development, according to which the inherited RB gene mutation is described as the first hit and the tumor-restricted mutation as the second hit. Back in 1947, Isaac Berenblum and Philippe Shubik discovered that chemical carcinogenesis consists of two stages: initiation and promotion.
1ĭespite massive research efforts and the very impressive progress made over the past several decades, full molecular understanding of cancer still remains a major challenge to the biomedical community. The alterations underlying tumorigenesis are considered to endow the evolving tumor with self-sufficiency of growth signals, insensitivity to antigrowth signals, evasion from programmed cell death, unlimited replicative potential, sustained angiogenesis, and finally, the ability to invade and metastasize. The evolution of a normal cell toward a cancerous one is a complex process, accompanied by multiple steps of genetic and epigenetic alterations that confer selective advantages upon the altered cells. Introduction: Mutations in p53 Are a Frequent Event in Cancer