P53 Mutation Panel 

p53 overview:
  • p53 is a tumour suppressor gene that play a vital role in maintaining the genomic stability and tumour prevention.
  • There are three major functions that are regulated by p53: DNA repair, apoptosis and cell cycle.
  • In normal cells without stress or stimuli, the activity of p53 is very low. Upon stress or multiple stimuli like chemotherapeutic agents, ionizing radiations or oncogenic stimuli can activate the p53 through a series of posttranslational modifications. In response to these stimuli p53 undergoes different changes and this activation could induce different affects depending the nature of the stimuli[1&2].
  • p53 is a transcription factor involved in the control of G1/S and G2/M phase transition, in DNA repair, and in induction of senescence, apoptosis, autophagy, mitotic catastrophe, and angiogenesis[3]
  • p53 is also responsible for regulating various metabolisms like glycolysis[4]
  • They key regulator of p53 gene is MDM2 and it has the ability to degrade the p53 protein by proteasome degradation pathway.
  • P53 regulates three major processes by controlling various target genes. They are: in DNA repair it regulates p53R2 and PIG3 genes, growth arrest is regulated by p21, Gadd45 and 14-3-3σ genes and in apoptosis it regulates Bax, Apaf-1 and PUMA genes [5, 6&7]
p53 mutations in Breast Cancer:
  • As mentioned earlier, p53 is the most frequently mutated gene that has been reported in almost all human cancers.
  • There are two major factors that cause p53 mutation i.e., endogenous (spontaneous changes arising in the base pairs during replication or can be due to the accumulation of mutations over a period of time) and exogenous (they are environmental factors such as over-exposure to radiations and stress).
  • When p53 mutates, its functions are altered as well, hence there will be a disturbance in the normal routine function of the normal p53.
  • Almost 50% of all human cancers has been reported the alteration of the p53 gene and its functions.
  • P53 mutations can be both somatic and germline. Somatic mutation is when somatic cells (body cells except cells in reproductive system) are mutated and germline mutation is when cells (reproductive cells) are mutated.
  • Somatic mutations cannot be passed on to the next generations as they are caused in the body cells. Unlike somatic mutation, germline mutations can be passed on to the next generation as the cells in the reproductive system are mutated.
  • Somatic p53 mutations are found in approximately 50% of human cancer [8&9]
  • Germline mutations in the TP53 gene cause a familial cancer predisposition
p53 Mutation Risk Factors in Breast Cancer:
  • About 30% of the breast cancer are a result of p53 mutation [10]
  • Breast tumours with positive staining for p53 are usually ER and PR negative [11]
  • Women who are carriers of germline mutations of TP53 gene are more likely to have HER2 amplification or overexpression [12]
  • Women who carry germline mutations in the TP53 gene have a very high risk of breast cancer of up to 85% by age 60 years.
  • Germline mutations in TP53 may cause an even higher risk of breast cancer, but these are much rarer than BRCA1/BRCA2 mutations [13]
  • Women with breast cancer diagnosed between the ages 30 and 40 may also have an increased risk of having a TP53 mutation.
  • It is estimated that about 4% to 8% of the patients who are diagnosed with the absence of BRCA mutation, have a likelihood of having TP53 mutation.
  • TP53 mutation in younger women with breast cancer is also increased with any of the following features:
  • A family history of cancer.
  • A personal history of a breast tumour that is positive for Estrogen (ER), Progesterone (PR) and HER2 receptors.
Other potential cancer risk associated to TP53 mutation:
  • There is a 90% lifetime risk for an individual to develop any type of cancer with TP53 mutation.
  • In a previous study of 200 cancer patients diagnosed with TP53 mutation, 15% developed second stage cancer, 4% developed third stage cancer and 2% developed a fourth stage cancer.
Recommended precautionary measures to watch for the development of cancer:
  • When a person is tested with TP53 mutation, the physician highly recommends regular monitoring to check the development of the cancer.
  • There are research evidences that shows that monitoring plan improves the survival of individual with a TP53 mutation who did not have any signs and symptoms of cancer.
  • Monthly breast self-examination, starting at the age of 18.
  • Clinical breast examination twice a year, annual breast MRI beginning at age 20 to 25.
References:
  1. He G, Siddik ZH, Huang Z, Wang R, Koomen J, Kobayashi R, et al., (2005). Oncogene, 24(18), 2929.
  2. Cox MLand Meek DW. (2010). Cellular Signalling, 22(3); 564–571
  3. Harris SL and Levine AJ. (2005). Oncogene, 24(17), 2899–2908.
  4. Warburg O. (1956). Science 123, 309-314.
  5. Levine AJ, Hu W, Feng Z. (2006). Cell Death Differ 13, 1027-1036.
  6. Riley T, Sontag E, Chen P, Levine A. (2008). Nat. Rev. Mol. Cell Biol. 9, 402-412.
  7. Vogelstein B, Lane D, Levine AJ. (2000). Nature 408, 307-310.
  8. Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M. (2007) Hum Mutat, 28, 622-629
  9. Soussi T, Ishioka C, Claustres M, Béroud C. (2006). Nat Rev Cancer 6, 83-90.
  10. Olivier M, Langerod A, Carrieri P, et al., (2006). Clinical Cancer Research, 12(4), 1157-1167.
  11. Sawaki M, Ito Y, Akiyama F et al., (2006). Breast Cancer, 13(2), 172-178.
  12. Melhem-Bertrandt A, Bojadzieva J, Ready KJ, Obeid E, Liu DD, Gutierrez-Barrera AM, et al., (2012). Cancer. 118(4), 908-913.
  13. Katherine Schon1 and Marc Tischkowitz. Clinical implications of germline mutations in breast cancer: TP53