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.

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.

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.

scholarly journals Pilot Study Assessing Tolerability and Metabolic Effects of Metformin in Patients With Li-Fraumeni Syndrome

2020 ◽  
Vol 4 (6) ◽  
Author(s):  
Farzana L Walcott ◽  
Ping-Yuan Wang ◽  
Christine M Bryla ◽  
Rebecca D Huffstutler ◽  
Neha Singh ◽  
...  
Keyword(s):  
Growth Factor ◽  
Oxidative Phosphorylation ◽  
Risk Reduction ◽  
Mitochondrial Function ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Li Fraumeni Syndrome ◽  
Factor Binding ◽  
Pathogenic Variants ◽  
Li Fraumeni

Abstract Background Li-Fraumeni syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline TP53 pathogenic variants. Patients with LFS have increased oxidative phosphorylation capacity in skeletal muscle and oxidative stress in blood. Metformin inhibits oxidative phosphorylation, reducing available energy for cancer cell proliferation and decreasing production of reactive oxygen species that cause DNA damage. Thus, metformin may provide pharmacologic risk reduction for cancer in patients with LFS, but its safety in nondiabetic patients with germline TP53 pathogenic variants has not been documented. Methods This study assessed safety and tolerability of metformin in nondiabetic LFS patients and measured changes in metabolic profiles. Adult patients with LFS and germline TP53 variant received 14 weeks of metformin. Blood samples were obtained for measurement of serum insulin-like growth factor–1, insulin, and insulin-like growth factor binding protein 3. Hepatic mitochondrial function was assessed with fasting exhaled CO2 after ingestion of 13C-labeled methionine. Changes in serum metabolome were measured. All statistical tests were 2-sided. Results We enrolled 26 participants: 20 females and 6 males. The most common adverse events were diarrhea (50.0%) and nausea (46.2%). Lactic acidosis did not occur, and there were no changes in fasting glucose. Cumulative mean 13C exhalation was statistically significantly suppressed by metformin (P = .001). Mean levels of insulin-like growth factor binding protein 3 and insulin-like growth factor-1 were statistically significantly lowered (P = .02). Lipid metabolites and branched-chain amino acids accumulated. Conclusions Metformin was safe and tolerable in patients with LFS. It suppressed hepatic mitochondrial function as expected in these individuals. This study adds to the rationale for development of a pharmacologic risk-reduction clinical trial of metformin in LFS.

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.

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.

scholarly journals Is CHEK2 a moderate-risk breast cancer gene or the younger sister of Li-Fraumeni?

2020 ◽  
Vol 13 (9) ◽  
pp. e236435
Author(s):  
Dilanka L De Silva ◽  
Ingrid Winship
Keyword(s):  
Breast Cancer ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Pathogenic Variant ◽  
Treatment Modalities ◽  
Cancer Gene ◽  
Li Fraumeni Syndrome ◽  
Multiple Cancers ◽  
Li Fraumeni ◽  
Breast Cancer Gene

The CHEK2 gene is mostly considered as a moderate breast cancer gene with the result that many clinicians have a narrow focus. We present the 10-year journey of a man who had five different cancers and had iterative genetic testing including for Li-Fraumeni syndrome, eventually to discover a pathogenic variant in the CHEK2 gene, possibly explaining his numerous cancers. This diagnosis offered him closure which he had desperately sought for well over a decade. A pathogenic variant in the CHEK2 gene can potentially explain these cancers because of its function as a tumour suppressor gene. Consideration is warranted of what this means for individuals with CHEK2 variants who may develop multiple cancers, their prognosis and whether different treatment modalities such as chemotherapy, radiotherapy or target agents would need modification. We encourage more research into the many faces of the CHEK2 gene and the potential for predisposition to multiple cancers.

scholarly journals TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children

2018 ◽  
Vol 36 (6) ◽  
pp. 591-599 ◽  
Author(s):  
Maoxiang Qian ◽  
Xueyuan Cao ◽  
Meenakshi Devidas ◽  
Wenjian Yang ◽  
Cheng Cheng ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Treatment Outcomes ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasms ◽  
Loss Of Function ◽  
Childhood All ◽  
Li Fraumeni Syndrome ◽  
Pathogenic Variants ◽  
Second Malignant Neoplasms ◽  
Li Fraumeni

Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li-Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children’s Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0%) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P < .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P < .001) and were more likely to have hypodiploid ALL (65.4% v 1.2%; P < .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P < .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1% and 0.7% ( P < .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.

scholarly journals Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants

2020 ◽  
Author(s):  
Cristina Fortuno ◽  
Kristy Lee ◽  
Magali Olivier ◽  
Tina Pesaran ◽  
Phuong L. Mai ◽  
...  
Keyword(s):  
Cancer Surveillance ◽  
Current Evidence ◽  
Variant Classification ◽  
Breast Cancers ◽  
Li Fraumeni Syndrome ◽  
Pathogenic Variants ◽  
Germline Variant ◽  
Risk Of Malignancy ◽  
Adrenocortical Carcinomas ◽  
Original Strength

ABSTRACTGermline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome (LFS), an autosomal dominant cancer predisposition disorder associated with high risk of malignancy, including early onset breast cancers, sarcomas, adrenocortical carcinomas and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants has been shown to decrease mortality; therefore, accurate and consistent classification of variants across clinical and research laboratories is crucial to patient care. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were applied to twenty ACMG/AMP criteria while nine were deemed not applicable. The original strength level for ten criteria was also adjusted due to current evidence. Use of the TP53-specific guidelines and sharing of clinical data amongst experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% in comparison with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.

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