Fast track — ArticlesBiochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study
Introduction
Characterisation of heritable germline mutations in tumour suppressor genes or oncogenes offers the potential for genetic screening, with the goal of prevention, early detection, and improved prognosis for patients with inherited cancer susceptibility.
Li-Fraumeni syndrome is an autosomal dominantly inherited prototypic cancer predisposition syndrome characterised by a high frequency of soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, brain tumours, adrenocortical carcinoma, leukaemia, and other malignant diseases, which typically occur at an earlier age in affected individuals than in the general population.1, 2
The classic definition of Li-Fraumeni syndrome is an index patient (proband) with a sarcoma diagnosed before 45 years of age, who has a first-degree relative younger than 45 years of age with any cancer, and a first-degree or second-degree relative with any cancer before the age of 45 years or a sarcoma at any age.3 Less stringent criteria have been referred to as Li-Fraumeni-like syndrome.4, 5, 6 Constitutional mutations of the TP53 tumour suppressor gene are the primary underlying genetic alteration that predisposes individuals to the development of cancer.7, 8 Germline TP53 mutations occur in 70–83% of patients who meet the classic Li-Fraumeni syndrome criteria9, 10 and 29–35% of patients who meet the updated Chompret criteria.6, 11, 12
In TP53 mutation carriers, the lifetime risk of developing cancer has been estimated to be as high as 73% for male carriers, and 93% for female carriers.13 In view of these striking cancer risks, close surveillance of affected individuals to enable early detection of neoplasms and improve clinical outcomes seems imperative. However, the diverse range of tumours, variability of age at onset, generally weak TP53 mutation genotype–phenotype correlations, and absence of evidence for effectiveness of screening have largely discouraged this practice.14, 15, 16, 17
Clinical surveillance strategies have been established and successfully implemented for several cancer susceptibility syndromes.17 On the basis of available data, our own experience with these disorders, and detection strategies for patients with sporadic Li-Fraumeni syndrome component tumours,18, 19, 20 we developed a practical surveillance protocol that uses non-invasive biochemical and imaging modalities for the management of patients with this syndrome. Here we show the feasibility and potential clinical benefits of such a protocol.
Section snippets
Patients and study design
The protocol was implemented at The Hospital for Sick Children (Toronto, ON, Canada) on Jan 1, 2004, and has been adopted in several institutions across North America. We assessed eight families with Li-Fraumeni syndrome from whom sufficient clinical and molecular information was available. Patients were recruited from three centres: the Cancer Genetics Program at The Hospital for Sick Children, Division of Hematology/Oncology at Children's Hospital of Los Angeles (CA, USA), and Primary
Results
As of Nov 1, 2010, comprehensive clinical and molecular information was available for eight families, giving a total of 48 individual TP53 mutation carriers. Since the initiation of the surveillance protocol on Jan 1, 2004, TP53 mutation status was confirmed in 33 of these patients, 18 of whom decided to undergo surveillance and 16 decided not to undergo surveillance (one patient is included in both groups for malignancies diagnosed before and after the onset of surveillance). All patients
Discussion
Use of our surveillance protocol enabled the presymptomatic detection of malignancies with readily available and safe biochemical and imaging techniques in germline TP53 mutation carriers in families with Li-Fraumeni syndrome. Of 18 patients screened, ten asymptomatic tumours were detected in seven patients during a period of 6 years. Detected tumours included small, localised high-grade tumours, some of which are typically fatal, such as choroid plexus carcinoma.23 Low-grade and premalignant
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