Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome

Abstract

Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited condition caused by germline mutations of the tumor suppressor gene encoding p53, a transcription factor triggered as a protective cellular mechanism against different stressors. Loss of p53 function renders affected individuals highly susceptible to a broad range of solid and hematologic cancers. It has recently become evident that children and adults with LFS benefit from intensive surveillance aimed at early tumor detection. In October 2016, the American Association for Cancer Research held a meeting of international LFS experts to evaluate the current knowledge on LFS and propose consensus surveillance recommendations. Herein, we briefly summarize clinical and genetic aspects of this aggressive cancer predisposition syndrome. In addition, the expert panel concludes that there are sufficient existing data to recommend that all patients with LFS be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established. Specifically, the panel recommends adoption of a modified version of the "Toronto protocol" that includes a combination of physical exams, blood tests, and imaging. The panel also recommends that further research be promoted to explore the feasibility and effectiveness of these risk-adapted surveillance and cancer prevention strategies while addressing the psychosocial needs of individuals and families with LFS.

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

“…Patients with mosaic mutations should also benefit from surveillance protocols, such as those which have recently been elaborated for germline TP53 mutation carriers. These protocols are based, from the first year of age, on abdominal ultrasound every 6 months, annual total body MRI, annual brain MRI and in women from 20 years on annual breast MRI 46. Nevertheless, the benefits of such heavy protocols regardless to the psychological impacts might be questionable in these patients with mosaic TP53 mutations, as one cannot exclude that the mosaic mutation might be restricted to certain tissues.…”

Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions

“…LFS is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the TP53 gene, which encodes the critical TP53 tumor suppressor protein. LFS is characterized by a high risk for a number of tumor types, including acute leukemia (9,12). Indeed, leukemia was one of the defining cancers of LFS in its original descriptions and accounts for 3% to 5% of all LFS cancers (12,13).…”

“…For example, if a matched related HSCT is to be used, relatives who test negative for the familial TP53 mutation would be the preferred donors. In addition, knowing the germline TP53 mutation status of the patient may be a consideration in determining pretransplant conditioning regimens, particularly with respect to use of total body irradiation (9). Strategies for tumor surveillance have been described for LFS (7,12,18), but their impact on improving outcomes for those who develop leukemia remains unknown.…”

“…For a more comprehensive description of the leukemia-predisposing conditions, the readers are referred to Table 1 and several excellent recent reviews (2-7), some of which describe management suggestions for affected children (3) and adults (7). For recommendations regarding surveillance for solid tumors in those syndromes in which leukemia occurs among a spectrum of other cancers, see other articles in this CCR Pediatric Oncology Series (8)(9)(10)(11).…”

Screening with whole‐body magnetic resonance imaging in pediatric subjects with Li–Fraumeni syndrome: A single institution pilot study

“…These results are controversial, with many citing the “Toronto Protocol” as standard screening, and others suggesting that the risks and benefits of this approach are not well‐enough studied . An expert panel recently published consensus recommendations based upon individual institutional approach …”