Li -Fraumeni Syndrome and Pancreatic Cancer
Author: Marzan Khan, B.Sc.
Li-Fraumeni syndrome (LFS) is a condition that makes individuals prone to developing a wide variety of cancers that occur early on in life, the most common types being- soft tissue sarcoma, osteosarcoma, breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemia. (1) Pancreatic cancer is minimally associated with the condition. (2) A survey found the presence of pancreatic cancer in only 1% of 475 tumor samples collected from 91 families who were carriers of p53 mutations, with half of them having LFS. The incidence of breast cancer amongst them was the highest -24%. (2) Pancreatic carcinoma in LFS patients usually occurs in the later stages of life. (3)
The underlying cause of LFS is germline mutations in TP53 gene on chromosome 17p, that encodes the transcription factor p53, crucial in cell cycle regulation and the repair of damaged and/or abnormal cells. (4) In the majority of cases, this mutation is obtained by inheritance. (5) De-novo germline mutations in p53 occur in 7%-20% of the cases. (5)
A person showing symptoms of any type of cancer at an early age or having first or second-degree relatives with cancer are at risk of developing LFS. (5) That is why tracing family history is an important part of diagnosis in LFS patients. Genetic testing can confirm mutations present in the gene, however, there are controversial ethical issues regarding their use, particularly in children and fetuses.
In patients with LFS, it is important to control the manifestations of the disease. They should be monitored closely so that any new cancers that arise are diagnosed and treated during the early stages. (6) Patients are also at risk of developing radiation-induced second and third primary tumors. (6) Therefore, radiation and alkylating agents should be used minimally (6) People at risk can be cautioned to avoid exposure to carcinogens such as sunlight, cigarette smoke, and alcohol consumption. (5) Therapeutic approaches that are aimed at restoring wild-type p53 by gene therapy as well as reactivating non-functional p53 by the use of small-molecule drugs are currently being investigated in many cancers. (7) Unlike radiation therapy, these small-molecule drugs are non-toxic to healthy cells, thus eliminating the risk of forming new tumors.
So far, PRIMA-1 has proven to be quite effective at correcting non-functional p53. (8) PRIMA-1 is changed to its methylated form, PRIMA-1MET that forms covalent adducts to thiol groups in the mutated protein and modifies them. (8) As a result, p53 regains its ability to destroy malignant cells. (8) A research study also found that PRIMA-1 induces apoptosis and increases the sensitivity of pancreatic cancer cells to various chemotherapeutic agents. (9)
- Magali Olivier, David E. Goldgar, Nayanta Sodha, Hiroko Ohgaki, Paul Kleihues, Pierre Hainaut and Rosalind A. Eeles. Li-Fraumeni and Related Syndromes. Cancer Res October 15 2003 63 (20) 6643-6650 http://cancerres.aacrjournals.org/content/63/20/6643.abstract
- Kleihues P, Schauble B, zur Hausen H, et al. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 1997; 150:1-13 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858532/
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- Mishra B and Patel RR. Gene Therapy for Treatment of Pancreatic Cancer. Austin Therapeutics. 2014;1(1): 10. https://books.google.ca/books?id=NmBB5ZoKkk4C&pg=PA6&lpg=PA6&dq=connection+between+li+fraumeni+and+Pancreatic+cancer&source=bl&ots=H0iCeaPP0N&sig=pqJT1tPMR6C-NIig3S_NkFKFsD0&hl=en&sa=X&ved=0ahUKEwi4nLrgzuPQAhUUIWMKHS3wBoc4ChDoAQhNMAg#v=onepage&q=connection%20between%20li%20fraumeni%20and%20Pancreatic%20cancer&f=false
- Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni Syndrome. 1999 Jan 19 [Updated 2013 Apr 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. https://www.ncbi.nlm.nih.gov/pubmed/20301488
- Elisa Becze BA, ELS, 2011 Mar 1. An introduction to Li-Fraumeni Syndrome, Five-Minute-In-Service. http://connect.ons.org/columns/five-minute-in-service/an-introduction-to-li-fraumeni-syndrome
- Sorrell, A. D., Espenschied, C. R., Culver, J. O., & Weitzel, J. N. (2013).TP53Testing and Li-Fraumeni Syndrome: Current Status of Clinical Applications and Future Directions. Molecular Diagnosis & Therapy, 17(1), 31–47. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627545/
- Emily J. Lewis. PRIMA-1 as a cancer therapy restoring mutant p53: a reviewBioscience Horizons (2015) 8: hzv006 http://biohorizons.oxfordjournals.org/content/8/hzv006.full
- Izetti, Patricia, Agnes Hautefeuille, Ana Lucia Abujamra, Caroline Brunetto de Farias, Juliana Giacomazzi, Bárbara Alemar, Guido Lenz, et al. ‘PRIMA-1, a Mutant p53 Reactivator, Induces Apoptosis and Enhances Chemotherapeutic Cytotoxicity in Pancreatic Cancer Cell Lines’. Investigational New Drugs 32, no. 5 (October 2014): 783–94. https://www.ncbi.nlm.nih.gov/pubmed/24838627
Izetti, Patricia, Agnes Hautefeuille, Ana Lucia Abujamra, Caroline Brunetto de Farias, Juliana Giacomazzi, Bárbara Alemar, Guido Lenz, et al. ‘PRIMA-1, a Mutant p53 Reactivator, Induces Apoptosis and Enhances Chemotherapeutic Cytotoxicity in Pancreatic Cancer Cell Lines’. Investigational New Drugs 32, no. 5 (October 2014): 783–94
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