The Evolving Phenotype of Li-Fraumeni Syndrome

TON May 2016 Vol 9 No 3 - Genetic Counseling
Cristi Radford, MS, CGC

In the past few years, some of the classic phenotypes and associated cancer risk estimates of inherited cancer syndromes have been questioned. This is due partly to increased access to genetic testing as well as to the availability of next-generation sequencing (NGS) panels for inherited cancer. Such panels allow researchers and clinicians to analyze multiple genes at one time, and these genes are not always high on the differential list. As a result, an individual sometimes receives a genetic diagnosis for a syndrome for which his or her personal and family history only vaguely resembles the clinical definition. From a genetic counseling perspective, this creates quite the conundrum in developing risk management strategies. One of these syndromes is Li-Fraumeni syndrome (LFS), which is known for a strikingly young age at diagnosis and an association with a variety of cancers.

Frederick Li and Joseph Fraumeni first described LFS in 1969 by examining records of children with rhabdomyosarcoma.1 It was not until almost 20 years later that the classic clinical definition of LFS was formally established.2 This definition resulted from a study that characterized 24 families selected based on having a proband with a sarcoma diagnosed at age younger than 45 years, a first-degree relative with cancer diagnosed at age younger than 45 years, and another first- or second-degree relative in the lineage with cancer diagnosed at age younger than 45 years or a sarcoma diagnosed at any age. Based on the ascertainment criteria of these initial families, it should be no surprise that the classic clinical definition of LFS requires sarcoma and young age at diagnosis. The additional core cancers designated by the 1988 study included breast cancer, brain tumors, leukemia, and adrenocortical carcinoma. This original definition was based on clinical descriptions and was established prior to the association of LFS with mutations in the TP53 gene. However, to date, these core cancers still account for the majority of LFS-related tumors.3,4

Over time, families were identified that shared characteristics of these initial families but didn’t meet the 1998 definition. Two additional sets of clinical criteria emerged: the Birch criteria and the Eeles criteria. These criteria are also referred to as Li-Fraumeni–like criteria because they are slightly more relaxed definitions of the 1988 definition and identified families who resembled LFS.5 Various criteria also emerged to help guide clinicians on who should be tested for TP53 mutations. The criterion with the highest predictive value was the Chompret criteria, which were developed in 2001 from a French cohort of mutation carriers.6 These criteria have since undergone several revisions in an attempt to represent the broader recognition of individuals with LFS. However, as with many inherited cancer syndromes, for commercial insurance to cover genetic testing of the TP53 gene, a version of the above criteria needed to be met—criteria that evolved based on the descriptions of 4 families in 1969. Therefore, until the availability of inherited cancer panels, the majority of families identified as having LFS resembled established criteria, and established management guidelines seemed reasonable.

Then, in 2012, NGS panels for inherited cancer became commercially available, and families outside of the research setting began to be identified with few or no characteristics of LFS.5 It is possible such findings are caused by germline mosaicism, undisclosed or unknown family history information, or a de novo mutation5; however, these factors don’t explain all the cases. The identification of such “unexpected” or “atypical cases” brings more unanswered questions than answered ones, including: How should these individuals be managed? Are their cancer risks and cancer surveillance needs really the same as the classic LFS family?

One recent study suggested that it might be appropriate to stratify clinical management of LFS according to class of mutation.4 This study included more than 400 patients with LFS and an identifiable TP53 mutation. The researchers found that the average age at which cancer presented was substantially lower among those who had a “dominant-negative” missense mutation (21.3 years) compared with those with all types of loss-of-function mutations (28.5 years) or genomic rearrangements (35.8 years). With the exception of children with adrenocortical carcinoma, most affected children had dominant-negative missense mutations. Additionally, cancer types among children and adults differed, with the main cancer types among children being osteosarcomas, adrenocortical carcinomas, central nervous system tumors, and soft tissue sarcomas, whereas among adults, the main cancer types were breast cancer and soft tissue sarcomas. There was a high rate (43%) of multiple malignancies, and for those carriers with medical records available who had been treated with radiotherapy, 30% developed a secondary tumor within the radiation field, thus providing additional evidence that chemotherapy and radiotherapy may contribute to the development of secondary tumors in LFS. Furthermore, among breast cancer survivors, almost one-third developed a contralateral breast cancer.

As the use of multigene tests, whole-exome sequencing, and whole-genome sequencing of both patients and patients’ tumors increases, the number of individuals found to have a TP53 mutation will increase, and the phenotype of LFS will likely greatly evolve. The Bougeard study4 described previously reviews one of the largest, if not the largest, series of TP53 mutation carriers in the world and provides useful insight into the clinical presentation and risk estimates of LFS. It is likely this information will be incorporated into future medical management guidelines. However, the patients studied were identified using primarily the 2009 version of the Chompret criteria and are not necessarily reflective of the “atypical” cases being identified in clinical practice today. These atypical cases will likely challenge our current view of LFS, as well as penetrance estimates and medical management strategies. In order to personalize and appropriately tailor medical management, additional studies are needed to better understand the cancer risks associated with TP53 mutations, as well as how cancer presents among individuals unexpectedly found to have a TP53 mutation. It will be interesting to see if the suggestion of stratifying clinical management of LFS according to mutation class is validated by future studies and implemented into clinical practice.

1. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms: a familial syndrome? Ann Intern Med. 1969;71:747-752.
2. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358-5362.
3. Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni­ syndrome. GeneReviews website. Updated April 11, 2013. Accessed January 31, 2016.
4. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33:2345-2352.
5. Kamihara J, Rana HQ, Garber JE. Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat. 2014;35:654-662.
6. Sorrell AD, Espenschied CR, Culver JO, Weitzel JN. Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome: current status of clinical applications and future directions. Mol Diagn Ther. 2013;17:31-47.

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Last modified: May 24, 2016