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Notes

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I updated the diagnosis section, clarified the information, and added citations. LyndzieB (talk) 02:25, 17 November 2016 (UTC)

I updated the pathology section with citations and new information and added citations to the epidemiology section. Clw45f (talk) 02:16, 17 November 2016 (UTC)

I plan to update the diagnosis section of the Li-Fraumeni syndrome page by including citations that are need for that section. LyndzieB (talk) 00:18, 17 November 2016 (UTC)

I plan to edit the characteristics section. I plan to include information about mode of inheritance, symptoms, and genotype-phenotype correlations. Arm7wb (talk) 02:16, 17 November 2016 (UTC)

I added the discovery of gene section, including a scientific history of the TP53 gene and its related protein. Mmh3k5 (talk) 07:32, 18 November 2016 (UTC) I updated the clinical and management sections with new information and citations artxw9 (talk) 00:43, 17 November 2016 (UTC)

Italic text

Characteristics

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Li-Fraumeni syndrome is characterized by early-onset presentation of various tumors in multiple organs at a young age.[1] Arm7wb (talk) 02:18, 17 November 2016 (UTC) It is seen typically in children and young adults, before the age of 30 years.[1] Arm7wb (talk) 02:19, 17 November 2016 (UTC) However, older adults can present with tumors into their 50's.[1] Arm7wb (talk) 02:18, 17 November 2016 (UTC)

Mode of Inheritance

Li-Fraumeni syndrome is characterized by autosomal dominant inheritance. [1]Arm7wb (talk) 01:26, 17 November 2016 (UTC) An individual with one affected parent has a 50% chance of inheriting the TP53 gene mutation.[1] Arm7wb (talk) 01:26, 17 November 2016 (UTC) If an individual has the genetic mutation on TP53, they have a 50% chance of passing the genetic defect on to their offspring. [1]Arm7wb (talk) 01:26, 17 November 2016 (UTC)

Symptoms

Individuals with Li-Fraumeni syndrome typically present with various tumors in multiple organs. [1] Arm7wb (talk) 02:19, 17 November 2016 (UTC) Li-Fraumeni syndrome (LFS) occurs when affected individuals are extremely vulnerable to developing classic tumors. [1] Arm7wb (talk) 00:46, 17 November 2016 (UTC) Arm7wb (talk) 02:18, 17 November 2016 (UTC) Such cancers include, but are not limited to, soft tissue and bone sarcomas, breast cancer, brain tumors and adrenocortical carcinomas. [1]Arm7wb (talk) 00:58, 17 November 2016 (UTC) Arm7wb (talk) 01:38, 17 November 2016 (UTC) These cancers are classified as core cancers to LFS. [1] Arm7wb (talk) 02:18, 17 November 2016 (UTC) Many other non-core cancers have been noted such as gastrointestinal, genitourinary and lung cancers as well as leukemias and lymphomas. [1] Arm7wb (talk) 01:38, 17 November 2016 (UTC)

Discovery of Gene

Early investigations of the TP53 gene began in 1979, when several independent groups of researchers unintentionally discovered the p53 protein, encoded by TP53, while studying Simian virus 40 cells.[2] The groups observed that the p53 protein complexes with the large T-antigen of the SV40 virus.[2] Cancer-derived cells showed overexpression of p53. [3] Mmh3k5 (talk) 07:32, 18 November 2016 (UTC)

In the 1980s, researchers began to clone cDNA of the p53 protein in both humans and mice.[3] These studied showed that transfection of p53 helped to transform cells, and that knock-out of p53 hindered cell proliferation.[3] Therefore, TP53 became acknowledged as a cellular oncogene that causes cancer. [2] Mmh3k5 (talk) 07:32, 18 November 2016 (UTC)

The year 1989 was a turning point; scientists realized that all previous research demonstrating oncogenic activity used mutated TP53 genes.[3] Lavigueur conducted a study on transgenic mice carrying a mutant TP53 gene, in which one-fifth of these mice developed a form on lung cancer.[4] Levine and his team of researchers cloned wild-type cDNA of the gene, which was lacking oncogenic activity and the ability to transform cells.[4] The wild-type p53 protein displayed anti-proliferative properties.[4] The TP53 gene was shown to be inactivated in numerous human cancer cells. [3] Mmh3k5 (talk) 07:32, 18 November 2016 (UTC)

TP53 was no longer acknowledged as an oncogene, but a tumor suppressor gene since its sustained function is necessary to prevent cancer.[3] Mmh3k5 (talk) 07:32, 18 November 2016 (UTC)

Genotype-Phenotype Correlation

Various genotype-phenotype correlations have been noted in LFS patients with the TP53 genetic mutation. [1]Arm7wb (talk) 02:18, 17 November 2016 (UTC) Missense mutations lead to development of various cancers earlier in age than what is typically seen in LFS. [1]Arm7wb 161.130.188.98 (talk) 17:14, 30 November 2016 (UTC) Increased risk for brain tumors is seen when the mutant TP53 gene occur in the DNA-binding loop [1]Arm7wb 161.130.188.98 (talk) 17:14, 30 November 2016 (UTC) Increased risk for adrenocortical carcinoma (ACC) are seen when the TP53 gene mutation occurs in the protein-DNA contact surface that is opposite to these DNA-binding loops. [1]Arm7wb 161.130.188.98 (talk) 17:14, 30 November 2016 (UTC)

Epidemiology

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Studies have shown frequency of occurrence for the p53 mutation to be around 1 in 5,000 individuals[5] Clw45f (talk) 01:42, 17 November 2016 (UTC)

Add citation to this sentence: "Over half of the cancers in Li-Fraumeni families had been previously associated with inactivating mutations of the p53 gene" [6] Clw45f (talk) 02:21, 17 November 2016 (UTC)

Pathology

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Add these citations to the information on the wiki page: Clw45f (talk) 01:23, 17 November 2016 (UTC)

"This unique feature may contribute to why families with this particular mutation often show incomplete penetrance." [5]Clw45f (talk) 02:04, 17 November 2016 (UTC)

"TP53 is a tumor suppressor gene on chromosome 17 that normally assists in the control of cell division and growth through action on the normal cell cycle" [7] Clw45f (talk) 00:44, 17 November 2016 (UTC) Clw45f (talk) 01:23, 17 November 2016 (UTC)

"CHK2 is also a tumor suppressor gene."[7] Clw45f (talk) 01:23, 17 November 2016 (UTC)

LFS-like families do not have a mutation in p53 gene [5] Clw45f (talk) 01:36, 17 November 2016 (UTC) [5] Clw45f (talk) 01:33, 17 November 2016 (UTC)

"The repair of "bad" DNA, or the apoptosis of a cell, prevents the proliferation of damaged cells." Clw45f (talk) 02:08, 17 November 2016 (UTC) [8]

"Mutated p53 proteins are typically more stable than wild-type, and can inhibit the activity of the wild-type protein in suppressing cell proliferation and in inducing cell cycle arrest." [9] Clw45f (talk) 02:12, 17 November 2016 (UTC)

New information: Clw45f (talk) 01:23, 17 November 2016 (UTC)

A majority of families have been found to have variant mutation in TP53 gene. Those that don't have TP53 variant show clinical phenotypes different from LFS. [1] Clw45f (talk) 01:23, 17 November 2016 (UTC)

Most mutations are found in DNA binding domain of p53 gene in regions that are highly conserved. [5] Clw45f (talk) 01:49, 17 November 2016 (UTC)

Protein Structure/Molecular Interactions:

TP53

Li-Fraumeni Syndrome demonstrates both allelic and locus heterogeneity, meaning that different mutations both in different genes as well as at the same locus can produce similar phenotypes. Amino acid changes (missense mutations) in the DNA binding region of p53 are more commonly associated with brain malignancies where missense mutations elsewhere in the p53 tetramer are associated with adrenocortical carcinomas. [10]Mutations that occur outside of the DNA binding domain of p53 result in a milder phenotype, and are also associated with a later age of onset for tumor development. [11]Evidence for this phenomenon suggests that mutations outside of the DNA binding region disrupt p53’s transactivation properties. Transactivation refers to a protein’s action on other genes’ behavior. p53 complexes with mutated DNA which signals for the expression and localization of other proteins that function to fix the DNA site or initiate apoptosis. Mutations that interfere with the DNA binding domain, appear to cause a more serious phenotype by disrupting the transactivation properties of the p53 protein. [12] Mes455 (talk) 03:46, 29 November 2016 (UTC)mes455

From: "Normal Conditions"

"The repair of "bad" DNA, or the apoptosis of a cell, prevents the proliferation of damaged cells." [13] Mes455 (talk) 03:46, 29 November 2016 (UTC)mes455

CHEK2

CHEK1 and CHEK2 are both required to prevent cancer malignancy. In LFS-2, truncations or missense mutations in CHEK2 have resulted in a loss-of-function in which p53 is not phosphorylated by CHEK2 in response to DNA damage/cellular stress. [14] In the reported cases where CHEK2 is mutated, p53 is not mutated in the resulting tumors. [15] Mes455 (talk) 03:46, 29 November 2016 (UTC)mes455

Clinical

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Add this citation to the information from the wiki page: The classical LFS malignancies - sarcoma, cancers of the breast, brain and adrenal glands - comprise about 80% of all cancers that occur in this syndrome. The risk of developing any invasive cancer (excluding skin cancer) is ~50% by age 30 (1% in the general population) and is 90% by age 70. Early onset breast cancer accounts for 25% of all the cancers in this syndrome. This is followed by soft tissue sarcomas (20%), bone sarcoma (15%) and brain tumors - especially glioblastomas - (13%). Other tumours seen in this syndrome include leukaemia, lymphoma and adrenocortical carcinoma [16] artxw9 (talk) 00:43, 17 November 2016 (UTC)

Add this citation to the information from the wiki page: ~90% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years. Females with this syndrome have almost a 100% lifetime risk of developing cancer. This compares with 73% for affected males. The difference may be due to much smaller breast tissue in males as well as increased estrogen levels in females.[17] artxw9 (talk) 00:43, 17 November 2016 (UTC)

Add this citation to the information from the wiki page: 2%-3% of osteosarcomas, 9% rhabdomyosarcomas and 7%-20% patients with multiple primary tumors have p53 mutations [18] artxw9 (talk) 00:43, 17 November 2016 (UTC)

Add this citation to the information from the wiki page: Although most cases of this syndrome have early onset of cancer, cases have also been reported later in life [16] artxw9 (talk) 00:43, 17 November 2016 (UTC)

Diagnosis

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Add the citations to the following info from the Li-Fraumeni syndrome page:

Li–Fraumeni syndrome is diagnosed if the following three classical criteria are met:

the patient has been diagnosed with a sarcoma at a young age (below 45), a first-degree relative has been diagnosed with any cancer at a young age (below 45), and another first-degree or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age.[19] LyndzieB (talk) 00:58, 17 November 2016 (UTC)

Other criteria have also been proposed, such as the Birch criteria,[10][19] LyndzieB (talk) 02:10, 17 November 2016 (UTC)which require:

a proband with any childhood cancer or sarcoma, brain tumor or adrenal cortical carcinoma diagnosed before age 45, a first or second degree relative with a typical LFS malignancy (sarcoma, leukaemia, or cancers of the breast, brain or adrenal cortex) regardless of age at diagnosis, and/or a first or second degree relative with any cancer diagnosed before age 60.

In addition, there has been suggestion of an Eeles criterion:[11][19]LyndzieB (talk) 02:10, 17 November 2016 (UTC)

two first or second degree relatives with LFS-related malignancies at any age.LyndzieB (talk) 01:14, 17 November 2016 (UTC)

Add this clarification of the Criteria:

Li-Fraumeni-like syndrome (LFL) has two diagnosis definitions associated with it because the affected individuals do not meet the classical criteria. The two definitions include the Birch definition, also know as the LFL 1 definition and the Eeles definition, known as the LFL 2 definition.[19] LyndzieB (talk) 01:41, 17 November 2016 (UTC)

Add this new Chompret criteria of Li-Fraumeni Syndrome include one of the following:

1. A proband with a tumor of the Li-Fraumeni tumor spectrum diagnosed before the age of 46 and a first or second-degree relative with a Li-Fraumeni tumor that has been diagnosed before the age of 56 or has multiple tumors. The Li-Fraumeni tumor spectrum includes soft-tissue sarcomas, osteosarcomas, premenopausal breast cancer, brain tumors, adrenocortical carcinomas, leukemias, or bronchoalveolar lung cancer.

2. A proband with several tumors. Two of the tumors have to be from the Li-Fraumeni Spectrum and the first has to had been diagnosed before the age of 46.

3. A proband who has not previous family members with, but has been diagnosed with a adrenocortical carcinoma or choroid plexus tumor. [20]LyndzieB (talk) 02:02, 17 November 2016 (UTC)

Management

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Add this citation to the information from the wiki page: Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation [1]

Add this citation to the information from the wiki page: Once such a person is identified, early and regular screenings for cancer are recommended for him or her as people with Li–Fraumeni are likely to develop another primary malignancy at a future time (57% within 30 years of diagnosis) [21] artxw9 (talk) 00:43, 17 November 2016 (UTC)

Add this information into the wiki page: Before the Chompret criteria was developed in 2009, the widely accepted criteria (aka the classical criteria) was used to determine if an individual was a candidate for Li-Fraumeni syndrome. See Diagnosis section for the classical diagnosis criteria. Now that the Chompret criteria has been developed, either criteria can be used to diagnose an individual. The benefit of using the Chompret criteria is that it allows for a lower age cut off and a negative family history [22] artxw9 (talk) 00:43, 17 November 2016 (UTC)

Add this citation to the information from the wiki page: A 2009 revision of the traditional Chompret criteria for screening has been proposed[23] artxw9 (talk) 00:43, 17 November 2016 (UTC)

The remaining subsections (recommendations and suggestions) should be changed to reflect the following:

Recommendations[1] artxw9 (talk) 00:43, 17 November 2016 (UTC)

It is important to note that while no measures have been definitively proven as being beneficial for both children and adults, recommendations and suggestions should not be taken lightly.

  • Both children and adults should have annual physical examinations that are comprehensive for both skin and neurological examinations. Clinicians should be aware of the high risks for rare, early-onset cancers and also for second malignancies in cancer survivors.
  • Individuals need to pay close attention to any symptoms and illnesses that last for long periods of time, particularly abdominal pain, bone and joint pain, or head aches. When these symptoms arise, the individual should seek medical attention for an evaluation promptly.  
  • Women should have an annual breast MRI to scan and monitor for cancer. They should also undergo a twice-yearly breast examination starting at 20-25 years of age. The use of mammograms has been controversial because of radiation exposure and limited sensitivity. When included, annual mammograms should alternate with breast MRI, with one modality every six months.

Suggestions[1] artxw9 (talk) 00:43, 17 November 2016 (UTC)

  • Starting no later than age 25, adults should undergo routine screening for colorectal cancer with a colonoscopy every two to three years.
  • Individuals should be aware of the cancer pattern observed within their family in order to undergo organ-targeted surveillance.

References

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  1. ^ a b c d e f g h i j k l m n o p q r s Schneider, Katherine; Zelley, Kristin; Nichols, Kim E.; Garber, Judy (1 January 1993). "Li-Fraumeni Syndrome". GeneReviews(®). University of Washington, Seattle. Retrieved 17 November 2016.
  2. ^ a b c Soussi, Thierry (2016-11-19). "The history of p53". EMBO Reports. 11 (11): 822–826. doi:10.1038/embor.2010.159. ISSN 1469-221X. PMC 2966958. PMID 20930848.
  3. ^ a b c d e f Levine, Arnold J.; Oren, Moshe (2009-10-01). "The first 30 years of p53: growing ever more complex". Nature Reviews Cancer. 9 (10): 749–758. doi:10.1038/nrc2723. ISSN 1474-175X. PMC 2771725. PMID 19776744.
  4. ^ a b c Sorrell, April D.; Espenschied, Carin R.; Culver, Julie O.; Weitzel, Jeffrey N. (2016-11-19). "TP53 Testing and Li-Fraumeni Syndrome: Current Status of Clinical Applications and Future Directions". Molecular diagnosis & therapy. 17 (1): 31–47. doi:10.1007/s40291-013-0020-0. ISSN 1177-1062. PMC 3627545. PMID 23355100.
  5. ^ a b c d e Malkin, David (17 November 2016). "Li-Fraumeni Syndrome". Genes & Cancer. 2 (4): 475-484. doi:10.1177/1947601911413466. ISSN 1947-6019. Retrieved 17 November 2016. {{cite journal}}: More than one of |pages= and |page= specified (help)
  6. ^ Malkin, David (17 November 2016). "Li-Fraumeni Syndrome". Genes & Cancer. 2 (4): 475–484. doi:10.1177/1947601911413466. ISSN 1947-6019. Retrieved 17 November 2016.
  7. ^ a b Reference, Genetics Home. "Li-Fraumeni syndrome". Genetics Home Reference. Retrieved 17 November 2016.
  8. ^ Elmore, Susan (1 January 2007). "Apoptosis: A Review of Programmed Cell Death". Toxicologic pathology. 35 (4): 495–516. doi:10.1080/01926230701320337. ISSN 0192-6233. Retrieved 17 November 2016.
  9. ^ Rivlin, Noa; Brosh, Ran; Oren, Moshe; Rotter, Varda (17 November 2016). "Mutations in the p53 Tumor Suppressor Gene". Genes & Cancer. 2 (4): 466–474. doi:10.1177/1947601911408889. ISSN 1947-6019. Retrieved 17 November 2016.
  10. ^ Palmero, E., et al. 2010. “Tumor Protein 53 Mutations and Inherited Cancer: Beyond Li-Fraumeni Syndrome”. Current Opinion in Oncology. 22:64-69.
  11. ^ Palmero, E., et al. 2010. “Tumor Protein 53 Mutations and Inherited Cancer: Beyond Li-Fraumeni Syndrome”. Current Opinion in Oncology. 22:64-69.
  12. ^ Palmero, E., et al. 2010. “Tumor Protein 53 Mutations and Inherited Cancer: Beyond Li-Fraumeni Syndrome”. Current Opinion in Oncology. 22:64-69.
  13. ^ Hamzehloie, T. 2012. "The Role of Tumor Protein 53 Mutations in Common Human Cancers and Targeting the Murine Double Minute 2-P53 Interaction for Cancer Therapy". IJMS. 37:3-8
  14. ^ Hamzehloie, T. 2012. "The Role of Tumor Protein 53 Mutations in Common Human Cancers and Targeting the Murine Double Minute 2-P53 Interaction for Cancer Therapy". IJMS. 37:3-8
  15. ^ Hamzehloie, T. 2012. "The Role of Tumor Protein 53 Mutations in Common Human Cancers and Targeting the Murine Double Minute 2-P53 Interaction for Cancer Therapy". IJMS. 37:3-8
  16. ^ a b "Li-Fraumeni syndrome — CheckOrphan". www.checkorphan.org.
  17. ^ Malkin, David (17 November 2016). "Li-Fraumeni Syndrome". Genes & Cancer. 2 (4): 475–484. doi:10.1177/1947601911413466. ISSN 1947-6019.
  18. ^ "Li-Fraumeni Syndrome Study". lfs.cancer.gov.
  19. ^ a b c d Cite error: The named reference :2 was invoked but never defined (see the help page).
  20. ^ "Li-Fraumeni Syndrome: Background, Pathophysiology, Epidemiology". 2 June 2016.
  21. ^ "Li–Fraumeni syndrome". flipper.diff.org.
  22. ^ "Li-Fraumeni syndrome". www.uptodate.com.
  23. ^ Tinat, J.; Bougeard, G.; Baert-Desurmont, S.; Vasseur, S.; Martin, C.; Bouvignies, E.; Caron, O.; Paillerets, B. Bressac-de; Berthet, P.; Dugast, C.; Bonaiti-Pellie, C.; Stoppa-Lyonnet, D.; Frebourg, T. "2009 Version of the Chompret Criteria for Li Fraumeni Syndrome". Journal of Clinical Oncology. 27 (26): e108–e109. doi:10.1200/jco.2009.22.7967.
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