Liver Cancer P53 Mutation Panel 

p53 overview:
  • P53 is a tumor suppressor proteins also called as the “guardian of cells”.
  • Also help in protecting the body from DNA damage, progression of cancer and also help in maintaining gene integrity.
  • p53 acts as a defence in protecting the cell from being damaged due to various external factors such as chemicals, ionising radiations etc.
  • p53 is generally found in low levels but is increased greatly during DNA damage as an initiative measure.
  • In case of severe damage, it initiates the process of apoptosis thereby permanently removing the damage.
  • General mechanism of p53 is that it binds with the genome there by stimulating another functionally important gene for the production of p21, which interacts with CKD2-na cell division stimulating protein thereby inhibiting the cell from passing to the next stage of the cell division [1].
  • p53 restricts the tumor development by acting as the sensor of cellular stress by responding to wide range of signals including DNA damage, hypoxia, oncogene expression, nutrient deprivation etc.
 p53 mutation in Liver Cancer:
  • p53 plays a vital role in protecting the cells from becoming cancerous.
  • Mutational inactivation is one of the major causes of cancer formation and progression.
  • Over 50% of the cancer occurs due to the mutation in p53 gene.
  • Mutation will block the normal functioning of the p53 thereby leading to cancer formation, progression and can cause the cancerous cells to metastasize.
  • Generally, the mutations occurring at p53 gene is a missense mutation and majority of the mutations are found in the DNA-binding domain [1]
  • Most of the p53 mutations is found in the genetic condition termed as Li-Fraumeni syndrome [2]
  • The mutant p53 is more dangerous as it has a prolonged half-life of about 2-12 hours [3-5].
  • And also displays chemo-resistance property portraying its role in DNA damage response [6-8].
p53 mutation and risk factors in liver carcinoma:
  • Hepatocellular carcinoma is the 6th common cancer and also is the 3rd leading cause of cancer mortality globally.
  • This cancer mortality and incidence rate increases annually with an incidence rate of about one million cases registered per year [9]
  • Major risk factor of Hepatocellular carcinoma includes viruses such as HBV and HCV which attributes more than 80% of HCC worldwide [10].
  • p53 is found to be mutated in more than 50% of aflatoxin B1 induced HCC; 45% of HBV associated and 13% of HCV associated HCC [11].
  • Activation of p53 is considered to be the central event in the DNA-damage response and also in prognosis of HCC where the cell signalling is affected at multiple levels.
  • The mutation in p53 dependant senescence program in hepatic cells increases liver fibrosis and cirrhosis,
  • And also enhances the transformation of the adjacent epithelial cells into hepatocellular carcinoma [12]
  • Other risk factors include cigarette smoking and elevated alcohol consumption which increases liver toxicity [13&14]
  • Apart from the risk factors there are other genetic disorders like hemochromatosis which is an iron overload disease [15]
 Reference:
  1. Bethesda. (1998). National Center for Biotechnology Information, https://www.ncbi.nlm.nih.gov/books/NBK22268/)
  2. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/p53-gene
  3. (Crawford LV, Pim DC, Lamb P. (1984). The cellular protein p53 in human tumours. Mol. Biol. Med. 2:261–272
  4. Cattoretti G, Rilke F, Andreola S, D'Amato L, Delia D. (1986). P53 expression in breast cancer. Int. J. Cancer. 1986;41:178–183 ;
  5. Chen PL, Chen YM, Bookstein R, Lee WH. (1990). Genetic mechanisms of tumor suppression by the human p53 gene. Science. 250:1576–80
  6. Vogelstein B, Kinzler KW. (1992). p53 function and dysfunction. Cell. 70:523-526.
  7. Velculescu VE, and El-Deiry WS. (1996). Biological and clinical importance of the p53 tumor suppressor gene. Clin. Chem.42:858-868;
  8. Vogelstein B, Lane D, Levine AJ. (2000). Surfing the p53 network. Nature. 408:307-310.
  9. Torre LA, Bray F, Siegel RL, et al. (2015). Global cancer statistics, 2012. CA Cancer J Clin 65:87-108.
  10. Wang XW, Hussain SP, Huo TI, Wu CG, Forgues M, Hofseth LJ et al. (2002). Molecular pathogenesis of human hepatocellular carcinoma. Toxicology 181-182: 43-47.
  11. Shiraha H, Yamamoto K, Namba M. (2013). Human hepatocyte carcinogenesis. Int J Oncol, 42:1133-8.
  12. Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, et al. (2013). Non-cell-autonomous tumor suppression by p53. Cell. 153(2):449-460. 
  13. Kew MC. (2003). Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis. Liver Int 23: 405-409.
  14. Yu MC, and Yuan JM. (2004). Environmental factors and risk for hepatocellular carcinoma. Gastroenterology 127: S72-S78.
  15.   Kowdley KV. (2004). Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology127: S79-S86.