scholarly journals Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes

2020 ◽  
Vol 28 (10) ◽  
pp. 1379-1386 ◽  
Author(s):  
Thierry Frebourg ◽  
◽  
Svetlana Bajalica Lagercrantz ◽  
Carla Oliveira ◽  
Rita Magenheim ◽  
...  
Keyword(s):  
Clinical Examination ◽  
Brain Mri ◽  
Soft Tissue Sarcomas ◽  
Abdominal Ultrasound ◽  
Dominant Negative ◽  
Whole Body ◽  
Breast Cancers ◽  
Li Fraumeni Syndrome ◽  
Cancer Predisposition Syndrome ◽  
Li Fraumeni

Abstract Fifty years after the recognition of the Li–Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i) 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 (hTP53rc) syndrome; (ii) the interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction, and functional data; (iii) 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; (iv) whole-body MRI (WBMRI) allows early detection of tumours in variant carriers and (v) 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.

scholarly journals Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0251639
Author(s):  
Camila Matzenbacher Bittar ◽  
Yasminne Marinho de Araújo Rocha ◽  
Igor Araujo Vieira ◽  
Clévia Rosset ◽  
Tiago Finger Andreis ◽  
...  
Keyword(s):  
Soft Tissue Sarcomas ◽  
Pathogenic Variant ◽  
Southern Brazil ◽  
Premenopausal Breast Cancer ◽  
Li Fraumeni Syndrome ◽  
Cancer Predisposition Syndrome ◽  
Pathogenic Variants ◽  
Li Fraumeni ◽  
Group B ◽  
Adrenocortical Carcinomas

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by pathogenic germline variants in the TP53 gene, characterized by a predisposition to the development of a broad spectrum of tumors at an early age. The core tumors related to LFS are bone and soft tissue sarcomas, premenopausal breast cancer, brain tumors, adrenocortical carcinomas (ACC), and leukemias. The revised Chompret criteria has been widely used to establish clinical suspicion and support TP53 germline variant testing and LFS diagnosis. Information on TP53 germline pathogenic variant (PV) prevalence when using Chompret criteria in South America and especially in Brazil is scarce. Therefore, the aim of this study was to characterize patients that fulfilled these specific criteria in southern Brazil, a region known for its high population frequency of a founder TP53 variant c.1010G>A (p.Arg337His), as known as R337H. TP53 germline testing of 191 cancer-affected and independent probands with LFS phenotype identified a heterozygous pathogenic/likely pathogenic variant in 26 (13.6%) probands, both in the DNA binding domain (group A) and in the oligomerization domain (group B) of the gene. Of the 26 carriers, 18 (69.23%) were R337H heterozygotes. Median age at diagnosis of the first tumor in groups A and B differed significantly in this cohort: 22 and 2 years, respectively (P = 0.009). The present study shows the clinical heterogeneity of LFS, highlights particularities of the R337H variant and underscores the need for larger collaborative studies to better define LFS prevalence, clinical spectrum and penetrance of different germline TP53 pathogenic variants.

Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers

2015 ◽  
Vol 33 (21) ◽  
pp. 2345-2352 ◽  
Author(s):  
Gaëlle Bougeard ◽  
Mariette Renaux-Petel ◽  
Jean-Michel Flaman ◽  
Camille Charbonnier ◽  
Pierre Fermey ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Soft Tissue Sarcomas ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Li Fraumeni Syndrome ◽  
Tumor Onset ◽  
Mutation Carriers ◽  
The Mean ◽  
Li Fraumeni

Purpose The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. Patients and Methods From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. Results The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. Conclusion The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.

Neuroradiology Manifestations of Li-Fraumeni Syndrome: Epidemiology, Genetics, Imaging Findings, and Management

Neurographics ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 228-235
Author(s):  
S. Naganawa ◽  
T. Donohue ◽  
A. Capizzano ◽  
Y. Ota ◽  
J. Kim ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Soft Tissue Sarcomas ◽  
Suppressor Gene ◽  
Imaging Findings ◽  
Li Fraumeni Syndrome ◽  
Increased Risk ◽  
Li Fraumeni ◽  
Risk Of Cancer

Li-Fraumeni syndrome is a familial cancer predisposition syndrome associated with germline mutation of the tumor suppressor gene 53, which encodes the tumor suppressor p53 protein. Affected patients are predisposed to an increased risk of cancer development, including soft-tissue sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma, among other malignancies. The tumor suppressor gene TP53 plays an important, complex role in regulating the cell cycle, collaborating with transcription factors and other proteins. The disruption of appropriate cell cycle regulation by mutated TP53 is considered to be the cause of tumorigenesis in Li-Fraumeni syndrome. Appropriate surveillance, predominantly by using MR imaging, is used for early malignancy screening in an effort to improve the survival rate among individuals who are affected. Patients with Li-Fraumeni syndrome are also at increased risk for neoplasm development after radiation exposure, and, therefore, avoiding unnecessary radiation in both the diagnostic and therapeutic settings is paramount. Here, we review the epidemiology, genetics, imaging findings, and the current standard surveillance protocol for Li-Fraumeni syndrome from the National Comprehensive Cancer Network as well as potential treatment options.Learning Objective: Describe the cause of second primary malignancy among patients with Li-Fraumeni syndrome.

Li-Fraumeni Syndrome and Whole-Body MRI Screening: Screening Guidelines, Imaging Features, and Impact on Patient Management

2021 ◽  
Vol 216 (1) ◽  
pp. 252-263
Author(s):  
Nikita Consul ◽  
Behrang Amini ◽  
Juan Jose Ibarra-Rovira ◽  
Katherine J. Blair ◽  
Tanya W. Moseley ◽  
...  
Keyword(s):  
Patient Management ◽  
Whole Body ◽  
Imaging Features ◽  
Whole Body Mri ◽  
Li Fraumeni Syndrome ◽  
Screening Guidelines ◽  
Li Fraumeni

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

2017 ◽  
Vol 55 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Mariette Renaux-Petel ◽  
Françoise Charbonnier ◽  
Jean-Christophe Théry ◽  
Pierre Fermey ◽  
Gwendoline Lienard ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
De Novo ◽  
Multiple Primary Cancers ◽  
Breast Cancers ◽  
De Novo Mutations ◽  
Li Fraumeni Syndrome ◽  
Medical Laboratories ◽  
Li Fraumeni ◽  
Adrenocortical Carcinomas ◽  
Generation Sequencing

BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS.Methods and resultsAmong 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35.ConclusionsThis study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.

scholarly journals PEComa in a Young Patient with Known Li-Fraumeni Syndrome

2015 ◽  
Vol 2015 ◽  
pp. 1-4 ◽  
Author(s):  
Kyriakos Neofytou ◽  
Simone Famularo ◽  
Aamir Z. Khan
Keyword(s):  
Risk Stratification ◽  
Tumour Suppressor Gene ◽  
Malignant Potential ◽  
Renal Lesion ◽  
Epithelioid Angiomyolipoma ◽  
Li Fraumeni Syndrome ◽  
Cancer Predisposition Syndrome ◽  
Rare Tumours ◽  
Li Fraumeni ◽  
The Right

Perivascular epithelioid cells neoplasms (PEComas) constitute a family of rare tumours which have been reported virtually in all anatomic sites. The histological clarification of the malignant potential of these tumours is still problematic despite the proposed risk stratification systems. Li-Fraumeni syndrome (LFS) is caused by a germline mutation in the TP53 tumour suppressor gene. It is a rare but well-characterized cancer predisposition syndrome leading to the development of a variety of different tumour types. To the best of our knowledge, an association between this syndrome and PEComas has not been previously documented. A 24-year-old lady with known LFS presented with two uncertain-in-nature lesions, one within the right part of the liver and one within the upper pole of the right kidney. The patient underwent an uncomplicated open simultaneous right partial nephrectomy and resection of segment 7 of the liver. The morphological and immunohistochemical features of both lesions were of epithelioid angiomyolipoma (PEComa). Although the obvious scenario was that the liver lesion was a metastasis from the renal lesion, the assessment of their malignant potential according to the existing risk stratification systems was rather in favour of two synchronous primary PEComas, pointing out that the histological assessment of malignant potential of PEComas is still problematic.

scholarly journals Whole-body magnetic resonance imaging of Li-Fraumeni syndrome patients: observations from a two rounds screening of Brazilian patients

2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Daniele Paixão ◽  
Marcos Duarte Guimarães ◽  
Kelvin César de Andrade ◽  
Amanda França Nóbrega ◽  
Rubens Chojniak ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Whole Body ◽  
Resonance Imaging ◽  
Li Fraumeni Syndrome ◽  
Body Magnetic Resonance Imaging ◽  
Li Fraumeni

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

2017 ◽  
Vol 65 (2) ◽  
pp. e26822 ◽  
Author(s):  
Allison F. O'Neill ◽  
Stephan D. Voss ◽  
Jyothi P. Jagannathan ◽  
Junne Kamihara ◽  
Callie Nibecker ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Pilot Study ◽  
Magnetic Resonance ◽  
Whole Body ◽  
Resonance Imaging ◽  
Single Institution ◽  
Li Fraumeni Syndrome ◽  
Body Magnetic Resonance Imaging ◽  
Li Fraumeni

scholarly journals Whole-Body MRI Surveillance—Baseline Findings in the Swedish Multicentre Hereditary TP53-Related Cancer Syndrome Study (SWEP53)

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 380
Author(s):  
Meis Omran ◽  
Emma Tham ◽  
Yvonne Brandberg ◽  
Håkan Ahlström ◽  
Claudia Lundgren ◽  
...  
Keyword(s):  
Brain Mri ◽  
Breast Mri ◽  
Whole Body ◽  
Surveillance Program ◽  
Malignant Tumours ◽  
Cancer Syndrome ◽  
Surveillance Strategy ◽  
Multi Centre Study ◽  
Whole Body Mri ◽  
Li Fraumeni Syndrome

A surveillance strategy of the heritable TP53-related cancer syndrome (hTP53rc), commonly referred to as the Li–Fraumeni syndrome (LFS), is studied in a prospective observational nationwide multi-centre study in Sweden (SWEP53). The aim of this sub-study is to evaluate whole-body MRI (WB-MRI) regarding the rate of malignant, indeterminate, and benign imaging findings and the associated further workup generated by the baseline examination. Individuals with hTP53rc were enrolled in a surveillance program including annual whole-body MRI (WB-MRI), brain-MRI, and in female carriers, dedicated breast MRI. A total of 68 adults ≥18 years old have been enrolled to date. Of these, 61 fulfilled the inclusion criteria for the baseline MRI scan. In total, 42 showed a normal scan, while 19 (31%) needed further workup, of whom three individuals (3/19 = 16%) were diagnosed with asymptomatic malignant tumours (thyroid cancer, disseminated upper GI cancer, and liver metastasis from a previous breast cancer). Forty-three participants were women, of whom 21 had performed risk-reducing mastectomy prior to inclusion. The remaining were monitored with breast MRI, and no breast tumours were detected on baseline MRI. WB-MRI has the potential to identify asymptomatic tumours in individuals with hTP53rc syndrome. The challenge is to adequately and efficiently investigate all indeterminate findings. Thus, a multidisciplinary team should be considered in surveillance programs for individuals with hTP53rc syndrome.

Sign in / Sign up

Export Citation Format

Share Document