Original articleLi-Fraumeni syndrome: report of a clinical research workshop and creation of a 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
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