p53 Mutation

p53 Mutations are criticial events in the progression to cellular dysfunction and carcinogenesis through cell cycle control loss.

- majority of p53 mutations occur in the DNA-binding core domain (DBD)

- DBD mutations prevent p53 from binding DNA and acting transcription factors

- these are termed recessive loss of function mutations

- homo-oligomerisation domain (OD) mutations, have a dominant nevative effect, as the abnormal p53 binds normal p53, unabling transcription activation

 

p53 Mutations in Human Cancers

From the study of Hollstein M et al., 1991. Science Jul 5; 253: 49-53.

- transition mutations are found in colon, lymphoid and brain cancers

- transitions are predominantly found at hot spots at CpG dinucleotides

- transversions of G:C to T:A are seen commonly in lung and liver cancers

- transversions are not localized to hot spots

- codon 249 p53 mutations are common in liver cancers with aflatoxin B1 and hapatitis B as risk factors

- A:T base pair mutations are seen in esophageal cancers

 

Li-Fraumeni Syndrome

- autosomal dominant inheritance of syndrome

- 50% of these patients have mutations in p53

- mutations consist of nonsense mutations and splice site mutations leading to short truncated proteins

- identification of this syndrome is through pattern of pathologies and laboratory investigation for mutations, mentioned above

- location of mutations are 17p13, site of TP53 and also 22q12

- patients have numerous tumors, these include: bone tumors, leukemia, sarcomas of the soft tissues, breast cancer, and brain tumors

- cancer risk is 50% by the age of 30

- treatment consists of early screening and annual blood counts