Abstract 1937P
Background
Fifty years after the recognition of the Li-Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed. Germline TP53 alterations are often identified among children with cancers, in particular soft-tissue sarcomas, adrenocortical carcinomas, central nervous system tumours or among adult females with early breast cancers, without familial history. This justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer syndrome.
Methods
The guidelines were elaborated on the basis of 337 published articles extracted from Pubmed.
Results
The interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction and functional data. The penetrance of germline disease-causing TP53 variants is variable, depending both on the type of variant (dominant-negative variants being associated with a higher cancer risk) and on modifying factors. Whole-body MRI (WBMRI) allows early detection of tumours in variant carriers and in cancer patients with germline disease-causing TP53 variants. Radiotherapy and conventional genotoxic chemotherapy contribute to the development of subsequent primary tumours. It is critical to perform TP53 testing before the initiation of treatment in order to avoid in carriers, if possible, radiotherapy and genotoxic chemotherapies. In children, the recommendations are to perform clinical examination and abdominal ultrasound every 6 months, annual WBMRI and brain MRI from the first year of life, if the TP53 variant is known to be associated with childhood cancers. In adults, the surveillance should include every year clinical examination, WBMRI, breast MRI in females from 20 until 65 years and brain MRI until 50 years. Table: 1937P
All patients who meet one modified “Chompret Criteria” should be tested for germline TP53 variants
| Familial presentation | TP53 core tumour (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumour, adrenocortical carcinoma) before 46 years AND at least one first- or second-degree relative with a core tumour before 56 years |
| Multiple tumours * | Multiple tumours, including 2 TP53 core tumours, the first of which occurred before 46 years |
| Rare tumours * | Adrenocortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma of embryonal anaplastic subtype |
| Very early-onset breast cancer * | Breast cancer before 31 years |
*irrespective of family history
Conclusions
This guideline do not signify nor intend to be a legal standard of care, it should support clinical decision making.
Clinical trial identification
Editorial acknowledgement
The authors deeply thank Matt Bolz-Johnson and Tom Kenny for logistic support, coordination of the meetings and permanent commitment for the elaboration of these guidelines. They are grateful to the following colleagues for their critical review of the guidelines: Prof. Lennart Blomqvist, Diagnostic Imaging Unit, Karolinska University Hospital, Stockholm, Sweden; Dr. Laurence Brugières, Department of Pediatrics and Adolescents Oncology, Gustave Roussy, Villejuif, France; Dr. Suzette Delaloge, Department of Medical Oncology, Gustave Roussy, Villejuif, France; Dr. Christian Kratz, Pediatric Hematology and Oncology, Medical School, Hannover, Germany. They also acknowledge their colleagues from the GENTURIS ERN for fruitful discussion and suggestions: Prof. Stefan Aretz, University Hospital, Bonn, Germany; Dr. Ignacio Blanco, Institut Català de la Salut, Barcelona, Spain; Maurizio Genuardi, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; Prof. Elke Holinski Feder, Medizinisch Genetisches Zentrum, Munich, Germany; Prof. Jan Lubinski, Pomeranian Medical University - University Clinical Hospital, Szczecin, Poland; Dr. Hector Salvador, Hospital Sant Joan de Déu, Barcelona, Spain; Dr Emma Woodward, St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. The GENTURIS ERN was co-funded by the European Union.
Legal entity responsible for the study
ERN-Genturis.
Funding
ERN-Genturis.
Disclosure
All authors have declared no conflicts of interest.