Li-Fraumeni syndrome (LFS) is a cancer predisposition caused by germline mutation of the TP53 gene (OMIM 151623). It is characterized by an early age of tumor onset and a broad tumor spectrum including sarcoma, breast cancer, brain tumor, and adrenocortical carcinoma.1 Due to this broad spectrum, surveillance of TP53 mutation carriers is challenging and whole-body magnetic resonance imaging (MRI) represents an attractive strategy.
To evaluate the pertinence of whole-body MRI, LIFSCREEN was designed as a national, multicenter randomized clinical trial. Participants were randomly allocated either to the standard screening procedures (clinical examination, abdomen and pelvis ultrasound, brain MRI, complete blood cell count, breast ultrasound and MRI for women >20 y) at inclusion and repeated yearly up to month 48, or to the same procedures with the addition of diffusion whole-body MRI. The main analysis on the primary end point is planned in 2017 when all participants will have at least 2 years of follow-up. We report here the cancers diagnosed so far in this large cohort of LFS families, regardless of the discovery modality.
Overall, 107 participants, 78 females and 29 males belonging to 75 different families, were enrolled (Table). The median age at inclusion was 32.9 years (range, 5-67 years). Fifty-one (48%) had a personal cancer history and 19 (18%) had developed more than 1 cancer. Chompret criteria for LFS2 were fulfilled for 84 participants (79%). Only 2 patients had no familial history of cancer. From November 2011 until September 2016, 15 patients underwent only 1 round of screening; 35, 2 rounds; 19, 3 rounds; 24, 4 rounds; and 7, 5 rounds. Overall in this 226.4 person-year population, 23 new primary cancers were diagnosed in 20 patients. Twelve cancers were detected at the first round. The median age at diagnosis was 39.8 years (range, 6-70 years). Ten cancers belonged to the core LFS spectrum (4 breast cancers, 2 sarcomas, 4 brain tumors), and 13 were outside: 5 lung adenocarcinomas (4 in never smokers and 1 in a light smoker), 2 leukemias, 1 choriocarcinoma, 1 renal carcinoma, 1 bifocal colon cancer, 1 myeloma, 1 pancreatic, and 1 bladder cancer. In addition, 3 relapses of a previous cancer (sarcoma, adrenal cortical carcinoma, breast cancer) were uncovered. The occurrence of a new primary cancer was not associated with personal cancer history (8 without cancer history, 12 with cancer history; P = .22, Fisher exact test).
As expected, brain tumors (4 of 23 [17%]) were frequent, as were breast cancers (4 of 23 [17%]), reflecting the predominance of females among recruited participants. Otherwise, only 2 new sarcomas were detected (9%), whereas these tumors are depicted as one of the most frequent LFS-related cancers.3,4 Thirteen of 23 cancers (57%) were outside the usual LFS core spectrum, with the most frequent being lung adenocarcinomas (5 of 23 [22%]). The proportion and diversity of off–core LFS spectrum cancers detected in TP53 mutation carriers as reported by others5,6 give growing evidence of a broader LFS spectrum, in agreement with the permissive role of TP53 mutations.2 Our observations seem to support recent moves toward broader cancer screening in TP53 mutation carriers.6 Data collection in the LIFSCREEN study is still ongoing. Our final analysis will help to determine the benefits and drawbacks (mostly related to false-positive test results) of whole-body MRI in TP53 mutation carrier surveillance. Studies focused on TP53 mutation penetrance, using methods limiting selection bias, are required to refine cancer risks to improve TP53 mutation carrier management.
Accepted for Publication: January 3, 2017.
Corresponding Author: Olivier Caron, MD, Département de Médecine Oncologique, Gustave Roussy Hôpital Universitaire, Université Paris-Saclay, 114 rue Edouard Vaillant, Villejuif F-94805, France (email@example.com).
Published Online: August 3, 2017. doi:10.1001/jamaoncol.2017.1358
Author Contributions: Dr Caron had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Caron, Frébourg, Foulon, Brugières.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Caron, Frébourg, Foulon, Brugières.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Foulon.
Obtained funding: Caron, Frébourg, Brugières.
Administrative, technical, or material support: Caron, Frébourg, Benusiglio, Brugières.
Supervision: Caron, Frébourg, Benusiglio, Brugières.
Conflict of Interest Disclosures: None reported.
Funding/Support: LIFSCREEN (NCT01464086) is funded by the French Ligue Contre le Cancer. Dr Benusiglio has received support from the Swiss National Foundation, grant 139844.
Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: The authors would like to thank the patients, their families, and all the LIFSCREEN investigators: Laurence Faivre, MD, PhD (Centre Hospitalier Universitaire Dijon, France), Catherine Dugast, MD, PhD (deceased), Caroline Abadie, MD (Hôpital Sud [CHU], Rennes, France), Valérie Bonadona, MD, PhD (Centre Léon Bérard, Lyon, France), Isabelle Coupier, MD, PhD, Pascal Pujol, MD, PhD (Centre Hospitalier Universitaire, Montpellier, France), Christine M. Maugard, MD, PhD (Hôpitaux Universitaires, Strasbourg, France), Emmanuelle Barouk-Simonet, MD (Institut Bergonié, Bordeaux, France), Capucine Delnatte, MD (Institut de Cancérologie de l’Ouest, Nantes, France), Yves-Jean Bignon, MD, PhD (Centre Jean Perrin/Equipe de Recherche sur les Traitements Individualisés des Cancers [ERTICa] EA4677, Clermont-Ferrand, France), François Eisinger, MD, PhD (Institut Paoli Calmettes, Marseille, France), Nathalie Chabbert-Buffet, MD, PhD (Assistance Publique, Hôpitaux de Paris, Tenon, France), Véronique Mari, MD (Centre Antoine Lacassagne, Nice, France), Hélène Dreyfus, MD (Institut Sainte Catherine, Avignon, France), Jean Chiesa, MD (Centre Hospitalier Universitaire, Nîmes, France), Paul Gesta, MD (Centre Hospitalier, Niort, France), Sophie Lejeune, MD (Centre Hospitalier Régional Universitaire, Lille, France), Viviane Feillel, MD (Centre Hospitalier Universitaire, Toulouse, France), and Sandra Canale, MD, Corinne Balleyguier, MD, PhD, Cédric Parlavecchio, Katty Malekzadeh, and Leonor Fasse, PhD, (Gustave Roussy Hôpital Universitaire, Villejuif, France).
Additional Information: This work is dedicated to the memory of our dear colleague Catherine Dugast.
JE. Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat
. 2014;35(6):654-662.PubMedGoogle ScholarCrossref
et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol
. 2015;33(21):2345-2352.PubMedGoogle ScholarCrossref
et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet
. 2010;47(6):421-428.PubMedGoogle ScholarCrossref
et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol
. 2009;27(8):1250-1256.PubMedGoogle ScholarCrossref
et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer
. 2016;122(23):3673-3681.PubMedGoogle ScholarCrossref
et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol
. 2016;17(9):1295-1305.PubMedGoogle ScholarCrossref