Elsevier

Cancer Genetics

Volume 205, Issue 10, October 2012, Pages 479-487
Cancer Genetics

Original article
Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium

https://doi.org/10.1016/j.cancergen.2012.06.008Get rights and content

Li-Fraumeni syndrome (LFS) is a rare dominantly inherited cancer predisposition syndrome that was first described in 1969. In most families, it is caused by germline mutations in the TP53 gene and is characterized by early onset of multiple specific cancers and very high lifetime cumulative cancer risk. Despite significant progress in understanding the molecular biology of TP53, the optimal clinical management of this syndrome is poorly defined. We convened a workshop on November 2, 2010, at the National Institutes of Health in Bethesda, Maryland, bringing together clinicians and scientists, as well as individuals from families with LFS, to review the state of the science, address clinical management issues, stimulate collaborative research, and engage the LFS family community. This workshop also led to the creation of the Li-Fraumeni Exploration (LiFE) Research Consortium.

Section snippets

A brief history and overview of LFS

LFS was first described in 1969 by Drs. Frederick Li and Joseph F. Fraumeni Jr. in a report of families with a variety of early-onset cancers, including childhood sarcomas and breast cancer in young adults (4). LFS is inherited in an autosomal dominant fashion, with a tendency for multiple primary cancers in affected individuals 5, 6. Although bone and soft tissue sarcomas, breast cancer, ACC, brain tumors, and leukemia remain the hallmarks of LFS, subsequent studies showed that the cancer

Clinical aspects of LFS—a global view

Recent studies in families from Southeastern Brazil who fulfilled LFS/LFL clinical criteria have identified a founder germline TP53 mutation that exhibits unusually high population prevalence (∼0.3%) 19, 20, 21, 22. This mutation, R337H (c.1010G>A, p.Arg337His), is in the oligomerization domain of the gene and was initially recognized to be the underlying cause of the high incidence of childhood ACC in Southern Brazil (23); however, carriers of this mutation appear to have a lifetime cumulative

Cancer screening in LFS

No international consensus on the appropriate clinical surveillance strategies in individuals with LFS has been established. Furthermore, the potential clinical benefits, psychosocial, societal and economic impact of a comprehensive clinical surveillance protocol utilizing frequent biochemical and imaging studies on early cancer detection and overall survival in asymptomatic TP53 mutation carriers remains unknown.

In the United Kingdom, no standard recommendation exists for LFS cancer screening.

TP53 in LFS

The TP53 gene was localized to chromosome 17p13.1 in 1986 and subsequently identified as the primary cause of LFS. Most deleterious germline mutations occur in the DNA binding domains, and somatic TP53 mutations are frequently seen in various cancer types. The p53 protein plays a critical role in a variety of cellular processes, including growth arrest, apoptosis or enhanced DNA repair in response to DNA damage and to multiple forms of cellular stress, and regulation of embryo implantation and

The TP53 mutation database

The TP53 Mutation Database is maintained by the IARC and is updated annually. The database consists of both germline and somatic TP53 mutations reported in the literature since 1989. It also contains information on the predicted effects on protein structure and function, and the number and type of cancers reported in families. At the time of this workshop, there were 535 germline mutations recorded from 532 families from North America, Europe, Japan, Brazil, and other countries (37). These data

Genetic counseling and psychosocial aspects of LFS

During the workshop, the speakers emphasized the importance of a detailed and accurate pedigree, which includes personal cancer history and family history over at least three generations. Counseling about LFS is a lifelong process that goes far beyond issues encountered in the initial counseling session and takes into account the informational and emotional needs of children and teenagers. The counseling process should include a discussion of cancer risk, the uncertainties in estimating risk,

Family support and advocacy

In an effort to bolster peer support, individuals with LFS and their family members were invited to participate in an informal gathering the previous evening as well as to attend the workshop to share their experiences related to LFS and their goals in attending the conference.

Two individuals with LFS and a member of an LFS family gave moving accounts of their experiences with this disorder (Box 1). In addition, a separate session was held in which members of various support and advocacy

Creation of the LiFE Research Consortium

In an effort to begin addressing the questions related to the complex clinical and basic science issues related to LFS, an international, multi-institution collaboration is needed. A consensus was reached on the key features of the research consortium.

Acknowledgments

We are grateful to the patients, families, and all attendees for their participation in this workshop. We thank Ms. Connie Lee of the Angioma Alliance, Mr. David Smith of Special Love, Inc., Mr. Kevin McQueen of the Fanconi Anemia Research Fund, Inc., and Mr. John Berkeley for their valuable contributions.

The workshop was supported by the NIH Office of Rare Diseases Research, the Division of Cancer Control and Population Sciences of the NCI, and the intramural research program of the Division

References (41)

  • S. Srivastava et al.

    Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome

    Nature

    (1990)
  • F.P. Li et al.

    Soft-tissue sarcomas, breast cancer, and other neoplasms: A familial syndrome?

    Ann Intern Med

    (1969)
  • E.D. Lustbader et al.

    Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients

    Am J Hum Genet

    (1992)
  • S. Fang et al.

    Effects of MDM2, MDM4 and TP53 codon 72 polymorphisms on cancer risk in a cohort study of carriers of TP53 germline mutations

    PLoS One

    (2010)
  • K.D. Gonzalez et al.

    Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations

    J Clin Oncol

    (2009)
  • F.P. Li et al.

    A cancer family syndrome in twenty-four kindreds

    Cancer Res

    (1988)
  • J.E. Garber et al.

    Follow-up study of twenty-four families with Li-Fraumeni syndrome

    Cancer Res

    (1991)
  • J.M. Birch et al.

    Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families

    Cancer Res

    (1994)
  • R.A. Eeles

    Germline mutations in the TP53 gene

    Cancer Surv

    (1995)
  • J.M. Varley

    Germline TP53 mutations and Li-Fraumeni syndrome

    Hum Mutat

    (2003)
  • Cited by (75)

    • Evolution of germline TP53 variant classification in children with cancer

      2022, Cancer Genetics
      Citation Excerpt :

      Five cancer types account for the majority of LFS tumors: adrenocortical carcinomas, breast cancer, central nervous system tumorss, osteosarcomas, and soft-tissue sarcomas. Hypodiploid acute lymphoblastic leukemia is suggestive of LFS, although hyperdiploid and diploid cases have been reported [3–5]. The diagnosis of LFS is established in a proband who meets classic LFS criteria and/or has a germline pathogenic variant in TP53 identified by molecular genetic testing [3].

    • Three Primary Tumors Including EGFR-mutated Non–Small Cell Lung Cancer as First Presentation in Patient With Li-Fraumeni Syndrome

      2021, Clinical Lung Cancer
      Citation Excerpt :

      In 45 unrelated Brazilian individuals with family histories fulfilling classic LFS criteria (Figure 4), 13 patients (28.8%) had TP53 mutations, of whom 6 (46.1%) were R337H.17 Carriers of TP53 R337H mutation differ in their clinical presentation with a 50% to 60% lifetime risk for cancer,18 and penetrance of cancer before age 30 is 15% to 20% compared with 50% in carriers of classic mutation.19 Lung adenocarcinoma occurs in only 3% to 5% of LFS.14,20

    • MicroRNA expression in relation with clinical evolution of osteosarcoma

      2020, Pathology Research and Practice
      Citation Excerpt :

      Osteosarcoma has two incidence peaks, people between 10–14 years old and adults around 65 years old. In the youngest it is usually primary and in the elder could be secondary to Paget’s disease [2–5]. The global incidence of osteosarcoma is 0.2–0.3/100,000 cases per year which increases to 0.8–1.1/100,000 cases per year in people between 15–19 years old [1].

    View all citing articles on Scopus
    View full text