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Table of Contents
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 1-5

Li–Fraumeni syndrome: A lesser known and investigated “cancer predisposition syndrome”

1 Department of Laboratory and Transfusion Services, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India; Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
2 Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India

Date of Web Publication26-Jun-2019

Correspondence Address:
Dr. Anurag Mehta
Departments of Laboratory and Transfusion Services and Research, Rajiv Gandhi Cancer Institute and Research Centre, Sector-V, Rohini, Delhi 110085
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCO.JCO_10_19

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How to cite this article:
Mehta A, Gupta G. Li–Fraumeni syndrome: A lesser known and investigated “cancer predisposition syndrome”. J Curr Oncol 2019;2:1-5

How to cite this URL:
Mehta A, Gupta G. Li–Fraumeni syndrome: A lesser known and investigated “cancer predisposition syndrome”. J Curr Oncol [serial online] 2019 [cited 2023 Nov 30];2:1-5. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2019/2/1/1/261469

Frederick P. Li, MD and Joseph F. Fraumeni, Jr., M.D. 1969: Described four families of a cancer predisposition syndrome that came to be called as Li–Fraumeni syndrome.

  Introduction Top

Li–Fraumeni syndrome (LFS, OMIM#151623) is a cancer predisposition syndrome with an autosomal-dominant inheritance and a high penetrance leading to an early onset of core cancers such as osteosarcoma, soft-tissue sarcomas, leukemia, brain tumors, including choroid papillary carcinoma of childhood, adrenal cortical carcinoma, and breast cancer.[1] Besides these core cancers, many other cancers are also seen more frequently in LFS-affected individuals compared to normal population. A total of 50% of the LFS cancers develop in children and young adults before 30 years of age.[2] Worse, victims of LFS can develop more than one cancer in their lifetime.[3] Treatment with radiation enhances the risk of developing cancer in carriers.[4] Treating physicians therefore must suspect and rule out LFS before treating a young patient with aforementioned cancers and sarcomas. The diagnosis of LFS is established by showing a deleterious germ line mutation in TP53 gene.

  Incidence of LFS Top

Pathogenic germ line TP53 mutations capable of causing LFS are rare with an estimated prevalence of 1/10,000–25,000 in the UK and USA. There are approximately 1000 multigenerational families worldwide with LFS.[5] No evidence of ethnic or geographic preference has been observed except a hot spot of LFS in Southern Brazil with a highly specific founder mutation “p. R337H.”[6] This mutation has been traced to a common ancestry from Portugal. Peculiarly, this mutation has a lower penetrance of 60% against extant observation of 100% penetrance in females and 73% penetrance in males globally.[7]

  Pathogenesis of LFS Top

Oncologists are familiar with high prevalence of somatic TP53 mutations (approximately 50%) in sporadic cancers and understand its consequences in terms of aggressive nature of such cancer and their relative resistance to treatment. Even in those cancers where TP53 somatic mutations are not demonstrable, many will have inactivation of p53 protein by alternative mechanisms.

LFS is, however, caused by germ line (inherited) deleterious mutations in TP53 gene. Rarely, this deleterious mutation may arise de novo in a sperm or ovum without previous history of LFS in the family. TP53 gene is a tumor suppressor gene (TSG) and its biallelic loss results in carcinogenesis. As a germ line (inherited) mutation is carried by all the somatic cells of the body, the second hit in accordance with Knudson two-hit hypothesis is relatively easy and early to occur resulting in high penetrance and early onset of cancers.[8] Remarkably, TP53 germ line mutation in a single allele (haploinsufficiency) has also been observed to raise the incidence of cancer. This is ascribed to tetrameric nature of functional p53 protein and any monomer contributed by abnormal TP53 allele can curtail or abrogate its function.

The TP53 gene has been referred to as “guardian of genome” and protects the normal cell from acquiring sublethal mutagenic genomic lesions. It is located on chromosome 17 (17p13). It carries 11 exons of which exon 1 is noncoding in the human TP53 gene. Eight messenger ribonucleic acid (mRNA) transcripts and 12 protein (p53) isoforms have been described [Figure 1].[9] These isoforms differ in cellular distribution and functional context. In normal physiological state, p53 is kept at low levels by its negative regulator Mdm2.
Figure 1: Structure of TP53 gene and p53 protein with functional domains. AD1 = activation domain 1, AD2 = activation domain 2, DBD = DNA-binding domain, OD = oligomerization domain, CTD = C-terminal domain, NES = nuclear exclusion signal, NLS = nuclear localization signal

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However, when the cell is exposed to stress such as hypoxia, nucleotides pool depletion, viral infection, oncogene activation, or oxidative stress or any other event leading to DNA damage, the negative control of Mdm2 is lifted and synthesis of p53, its accumulation and activation begins. Initial dimerization is followed by two dimers coupling together to produce a tetramer. This polymerization comes about by the action of “oligomerization domain” at C terminus of the p53 protein. The tetrameric p53 scans the genome for DNA damage through its all-important “DNA-binding domain” (DBD) and on identifying such damage, sends signals to the third component of p53 protein, the “transcription activation domain” (TAD) to initiate transcription of growth arrest genes, importantly CDKN1A, GADD45A, and RPRM. Although the cell cycle is halted, the next set of transcription activation happens in DNA repair gene such as ERCC5, FANCC, GADD45A, XRCC5, MGMT, MLH1, MSH2, RRM2B, PAPD7, and XPC.[10] An attempt is made to repair the damage and if successful, the cell proceeds and completes the cell cycle. However, if the process of repairs fails, the abnormal cell as a “last resort” is removed by apoptosis, activated by initiating transcription of proapoptotic genes such as Bax, Apaf-1, PUMA, and NoxA.

To surmise, p53 protein checks for genomic damage, identifies such damages, stops the cell cycle to complete the repair of the DNA damage, and in case, the damage is irreparable, eliminate such cell through apoptosis [Figure 2]. Failure of this process will allow cell with sublethal and mutagenic DNA alterations to continue through cell cycle, proliferate, and acquire further deleterious and carcinogenic mutations.
Figure 2: Functions of p53 protein. Cell cycle arrest, DNA repair, and apoptosis are crucial to genomic integrity and preclude escape of genetically damaged cell into cell cycle

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Pathogenic germ line mutation abrogates the function of p53 protein by the following:

  • Preventing oligomerization and thereby leading to synthesis of dysfunctional p53
  • Altering the DBD domain that causes failure to recognize the genetic alteration in the genome or fails to transmit signal to TAD to activate transcription of cell cycle arresting genes
  • Altering the TAD so that it no more responds to signals from DBD and fails to activate the transcription of its subordinate genes

  •   Nature of Germ Line Mutations in LFS Top

    The TP53 gene has been shown to carry over 250 pathogenic germ line mutations all across the TP53 gene but more thickly in exon 5–8 that codes for DBD of p53 protein. Mutations at eight hotspot codons are especially common [Figure 3] and all except one (at codon 337) reside in DBD. It has also been noted that germ line mutations are more frequent in CpG repeats and are mostly missense mutations (80%), unlike BRCA and MMR genes where frameshift and nonsense mutations dominate. Small indels have also been identified as pathogenic and similar to other “cancer predisposition syndromes” assigning pathogenicity to a genetic alteration is a challenging and a complex task.[11]
    Figure 3: Codon-wise distribution of pathogenic germ line mutations of TP53 gene. Adopted from IARC TP53 database[11],[12]

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      Method of Testing Top

    Sequencing of the entire exome with adjacent intronic sequences using next generation sequencing (NGS) is the method of choice for TP53 germ line mutation profiling. Though, duplication and deletions (long genomic rearrangements) are not identifiable by NGS, these are rare and account for approximately 1% of germ line deleterious alterations.[13],[14] The current literature and guidelines however recommend “Multiplexed Ligation Probe Amplification Assay” for identifying these large duplications and deletions.

      Who Should Be Tested? Top

    1. The individuals of the family with a pathogenic or suspected to be pathogenic TP53 mutations.

    2. An individual (proband) who fulfils all the following three sub-criteria:

      1. Is diagnosed with a sarcoma before 45 years of age.
      2. Has a first-degree relative with any cancer under 45 years of age.
      3. Has a first- or second-degree relative with any cancer under 45 years or sarcoma at any age.[15]

    3. More recently, Chompret criteria for TP53 testing[16],[17] have become more widely accepted and they simplify the selection of candidates for germ line testing for LFS/Li-Fraumeni-like (LFL) syndrome. The Chompret criteria are as following:

      1. An individual with LFS-spectrum tumor (soft tissue or osteosarcomas, brain tumors, premenopausal breast cancers, leukemia, Adrenocortical carcinoma (ACCs), and lung bronchoalveolar carcinomas, except breast cancer), 46 years of age, AND at least one first- or second-degree relative with an LFS tumor before 56 years of age or with multiple tumors at any age.


      2. Proband with multiple tumors (except multiple breast cancers), the first of which occurs before the age of 46 years, with at least two belonging to the LFS spectrum.


      3. Proband with an ACC or choroid plexus carcinoma regardless of family history.OR
      4. Breast cancer before 31 years of age.

        Management of a Mutation Carrier or a Cancer Survivor of LFS Top

      Managing a mutation carrier or a survivor of LFS is complex and no data exist with regard to actual survival or quality of life benefit of such strategies. It is however expected that some benefit may be accrued from adopting risk reduction approaches in the cancer survivor of LFS/LFL for a second malignancy and in the healthy carriers through prophylactic mastectomy in females and early diagnosis and prompt management of a neoplasm in all. Following measures have been recommended by National Comprehensive Cancer Network:[18]

      1. Breast cancer screening for women:

          1. Create self-awareness of changes in breasts beginning at the age of 18 years specially at the end of menses and advise the carrier to report any unusual changes to physician for prompt action.
          2. Perform clinical breast exam every 6 months starting at the age of 20 years.
          3. Advise annual breast magnetic resonance imaging (MRI) mammogram with contrast beginning at the age of 20 years or at the age of earliest breast cancer detected in the family, if that is before 20 years. X-ray mammography shall be avoided as exposure to radiation may increase the risk of cancer.
          4. From the 30th year onward, advise annual breast MRI and mammogram with consideration of tomosynthesis.
          5. Screening beyond 75 years should be considered on an individual basis.
      2. Breast cancer risk reduction for women:
          1. Offer a discussion on risk-reducing mastectomy. Following mastectomy, the screening shall continue as mentioned earlier.

      3. Additional cancer screening for men and women should be planned in the following form:

          1. Comprehensive physical examination including neurological examination and search for rare cancers and second malignancy in cancer survivors every 6–12 months.
          2. Detailed dermatological screening from 18 years onward.
          3. Annual whole-body MRI including MRI brain.
          4. Colonoscopy every 2–5 years starting at age 25.
          5. Additional screening based on family cancer history.
          6. The current guidelines are not clear on testing for TP53 germ line mutation in children below 18 years. The National Society of Genetic Counselors encourages deferring predictive testing but pediatrician must be alerted to the existence of LFS in the family and the associated risk of childhood cancers.[19]
          7. Educate “at-risk members” to “signs and symptoms” of cancer and address their psychosocial and quality of life issues through counseling.

      4. Reproductive options:
          1. For patients of reproductive age, advise about options for prenatal diagnosis and assisted reproduction including preimplantation genetic diagnosis.
      5. Risk to relatives:
          1. Advise relatives of their risk of inheritance and management if found positive for pathogenic mutation.
          2. Recommend genetic counseling and consideration of genetic testing for at-risk relatives.

        Conclusion Top

      LFS is a familial cancer predisposition syndrome. Core tumors and a range of other tumors develop with a lifetime risk of nearly 100% in affected females and slightly less in males. Testing for germ line mutation is suggested for individuals fulfilling criteria for Classic LFS or Chompret criteria for mutation testing. Risk reduction and management of LFS are complex and evolving issues as these interventions may not necessarily convert to survival or quality of life benefits. However, knowing and identifying LFS is essential as the progress at this step can only help us find and evaluate the best screening and risk-reducing approaches.

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      Conflicts of interest

      There are no conflicts of interest

        References Top

      Sorrell AD, Espenschied CR, Culver JO, Weitzel JN. Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome. Mol Diagn Ther 2013;17:31-47.  Back to cited text no. 1
      Kumar P, Gill RM, Phelps A, Tulpule A, Matthay K, Nicolaides T. Surveillance screening in Li-Fraumeni syndrome: Raising awareness of false positives. Cureus 2018;10.  Back to cited text no. 2
      Mai PL, Best AF, Peters JA, DeCastro RM, Khincha PP, Loud JT, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 2016;122:3673-81.  Back to cited text no. 3
      Nandikolla AG, Venugopal S, Anampa J. Breast cancer in patients with Li–Fraumeni syndrome—A case-series study and review of literature. Breast Cancer: Targets Ther 2017;9:207.  Back to cited text no. 4
      Who has LFS? Li–Fraumeni Syndrome Association [Internet]. Li-Fraumeni syndrome association. 2019. [cited 8 June 2019]. Available from: https://www.lfsassociation.org/what-is-lfs/who-has-lfs/. [Last accessed on 11 June 2019].  Back to cited text no. 5
      Ashton-Prolla P. Hereditary cancer syndromes: Opportunities and challenges. In: BMC Proceedings. BioMed Central 2013;7:K14.  Back to cited text no. 6
      McBride KA, Ballinger ML, Killick E, Kirk J, Tattersall MH, Eeles RA, et al. Li-Fraumeni syndrome: Cancer risk assessment and clinical management. Nat Rev Clin Oncol 2014;11:260.  Back to cited text no. 7
      Wang LH, Wu CF, Rajasekaran N, Shin YK. Loss of tumor suppressor gene function in human cancer: An overview. Cell Physiol Biochem 2018;51:2647-93.  Back to cited text no. 8
      Joruiz SM, Bourdon JC. p53 isoforms: Key regulators of the cell fate decision. Cold Spring Harb Perspect Med 2016;6:a026039.  Back to cited text no. 9
      Fischer M. Census and evaluation of p53 target genes. Oncogene 2017;36:3943.  Back to cited text no. 10
      Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: Origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010;2:a001008.  Back to cited text no. 11
      Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: Lessons from recent developments in the IARC TP53 database. Human Mutat 2007;28:622-9.  Back to cited text no. 12
      Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni syndrome. In: GeneReviews [Internet] Apr 11. Seattle, WA: University of Washington; 2013.  Back to cited text no. 13
      Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, et al. Beyond Li Fraumeni Syndrome: Clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009;27:1250-6.  Back to cited text no. 14
      Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;48:5358-62.  Back to cited text no. 15
      Chompret A, Abel A, Stoppa-Lyonnet D, BrugiÈres L, PagÈs S, Feunteun J, et al. Sensitivity and predictive value of criteria for p53germline mutation screening. J Med Genet 2001;38:43-7.  Back to cited text no. 16
      Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 2009;27:e108-9.  Back to cited text no. 17
      Nccn.org. 2019 [cited 12 June 2019]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. [Last accessed on 12 June 2019].  Back to cited text no. 18
      National Society of Genetic Counselors. Blogs: Genetic testing of minors for adult-onset conditions [Internet]. Nsgc.org. 2019 [cited 12 June 2019]. Available from: https://www.nsgc.org/p/bl/et/blogaid=860. [Last accessed on 12 June 2019].  Back to cited text no. 19


        [Figure 1], [Figure 2], [Figure 3]

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