Sensitive and quantitative TP53 variant calling by NGS

Tumor protein p53 function

Tumor protein p53 is encoded by the TP53 gene and is located on the short arm of chromosome 17 at position 13.1. p53 contains transcriptional activation, DNA binding, and oligomerization domains. The protein regulates the cell cycle and maintains genomic stability through many different mechanisms of action. The protein is localized in the nucleus where it functions as a transciption factor.

When DNA damage occurs due to radiation, ultra-violet light, genotoxic drugs, nutrition deprivation, or heat/cold shock, p53 is activated via the ATM-CHK2 or ATR-CHK1 DNA repair pathways. Cell nutrition deprivation and heat/cold shock can stimulate p53 directly through hypoxia and the subsequent production of nitric oxide. Once stimulated, p53 transctiptionally activates target genes1,2. The target genes can induce apoptosis, senescence, DNA repair, changes in metabolism, and cell cycle arrest. One p53 effector, p21, is a potent negative regulator of cell cycle progression and cell division, and its up regulation results in cell cycle arrest. Pausing the cell cycle gives the cell the opportunity to make repairs, if possible, or commit to p53-mediated cell death.

p53 mutations in cancer

Loss of p53 function through genetic mutations or disturbances in the p53-signaling pathway is a common feature in cancers. In fact, according to the International Cancer Genome Consortium, the TP53 gene is mutated in the majority of ovarian, esophageal, lung, rectal, pancreatic, oral, colon, and brain cancers. Greater than 75% of TP53 mutations result in expression of a mutant p53 protein that has lost some level of wild-type function3. Impaired p53 can inhibit downstream tumor suppression, resulting in uncontrolled neoplastic growth. p53 has been shown to gain oncogenic functions from genetic mutations in the TP53 gene4. The tumor-driving functions of mutant p53 include angiogenesis, stem cell expansion, survival, proliferation, enhanced chemo-resistance, mitogenic defects, metastasis, migration, and genomic instability5-8.

Detecting mutations using Archer® NGS tests

Having a technically strong next-generation sequencing (NGS) panel with simple and consistent library preparation is critical for variant detection. Archer® VariantPlex®next-generation sequencing (NGS) tests rapidly detect copy number variations (CNVs), single nucleotide variants (SNVs) and indels from DNA, including FFPE preserved specimens. Archer®’s proprietary Anchored Multiplex PCR (AMP™) chemistry allows for rapid preparation of highly multiplexed NGS libraries for targeted capture of mRNAs produced from fusion genes.

Archer’s AMP™ chemistry is also designed to be modular, enabling users to seamlessly add additional markers to an existing catalog panel without decreasing performance, or build a fully custom panel and update it as needed. The single gene VariantPlex® TP53 Test is available as an Archer® focus panel, or add TP53 to any existing Archer® VarianPlex panel. The Archer® VariantPlex® technology combines maximum gene coverage with robust enrichment chemistry and an easy-to-use workflow to give you confident, sensitive and quantitative TP53 variant calling, from library preparation through data analysis for Illumina® platforms.

Want to learn more about how Archer® VariantPlex® NGS tests detect TP53 mutations? Click here


References

  1. Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids res. 2000;28(1):27-30.
  2. Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M. Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res. 2014;42(Database issue):D199-D205. doi:10.1093/nar/gkt1076.
  3. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28(6):622-629. doi:10.1002/humu.20495.
  4. Strano S, Dell’Orso S, Mongiovi AM, et al. Mutant p53 proteins: between loss and gain of function. Head Neck. 2007;29(5):488-496. doi:10.1002/hed.20531.
  5. Liu DP, Song H, Xu Y. A common gain of function of p53 cancer mutants in inducing genetic instability. Oncogene. 2010;29(7):949-956. doi:10.1038/onc.2009.376.
  6. Lang GA, Iwakuma T, Suh Y-A, et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell. 2004;119(6):861-872
  7. Oliv KP, Tuveson DA, Ruhe ZC, et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004;119(6):847-860. doi:10.1016/j.cell.2004.11.004.
  8. Muller PAJ, Vousdan KH. p53 mutations in cancer. Nat Cell Biol. 2013;15(1):2-8. doi:10.1038/ncb2641.

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