-
Cold Spring Harbor Molecular Case... Feb 2019Li-Fraumeni syndrome (LFS) is an autosomal dominant condition associated with a high risk of a broad range of childhood- and adult-onset cancers. LFS is related to... (Review)
Review
Li-Fraumeni syndrome (LFS) is an autosomal dominant condition associated with a high risk of a broad range of childhood- and adult-onset cancers. LFS is related to germline mutations of the tumor-suppressor gene The most common reported leukemia associated with LFS is hypodiploid acute lymphoblastic leukemia, but myeloid malignancies including acute myeloid leukemia (AML), chronic myeloid leukemia, and myelodysplastic syndrome (MDS) are also reported, often in the setting of therapy-related disease. We reviewed the clinicopathologic characteristics including cytogenetics and molecular analysis for seven adult patients with LFS and hematologic malignancies evaluated at the Hereditary Hematologic Malignancy Clinic (HHMC) at MD Anderson Cancer Center. We present this LFS review series to increase awareness of LFS for the appropriate diagnosis of both patients and potentially affected relatives, as well as provide experience with patient outcomes in this difficult to treat population.
Topics: Adult; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Li-Fraumeni Syndrome; Male; Middle Aged; Myelodysplastic Syndromes; Pedigree; Tumor Suppressor Protein p53; Young Adult
PubMed: 30709875
DOI: 10.1101/mcs.a003210 -
Cold Spring Harbor Perspectives in... Apr 2017Li-Fraumeni syndrome (LFS) is a complex hereditary cancer predisposition disorder associated with early-onset cancers in diverse tissues of origin. Germline mutations... (Review)
Review
Li-Fraumeni syndrome (LFS) is a complex hereditary cancer predisposition disorder associated with early-onset cancers in diverse tissues of origin. Germline mutations are identified in 75% of patients with classic LFS. The lifetime likelihood of a mutation carrier developing cancer approaches 75% in males and almost 100% in females. Several genetic modifiers have been implicated to account for the phenotypic variability within and across LFS families; however, efforts to develop predictive algorithms of age of onset and type of cancers in individual patients have not yet found clinical use. Although it is not possible to prevent cancers from forming in LFS patients, novel protocols have been developed for surveillance for early tumor detection, leading to improvements in survival. Comprehensive studies of the genome and epigenome in LFS families in the context of germline mutations is anticipated to shed light on this intriguing, yet devastating, disease and to transform the clinical management of patients.
Topics: Animals; Disease Models, Animal; Family; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Li-Fraumeni Syndrome; Mice; Tumor Suppressor Protein p53
PubMed: 28270529
DOI: 10.1101/cshperspect.a026187 -
Cancers Jul 2022Li-Fraumeni syndrome (LFS) is a rare familial tumor predisposition syndrome with autosomal dominant inheritance, involving germline mutations of the tumor suppressor... (Review)
Review
Li-Fraumeni syndrome (LFS) is a rare familial tumor predisposition syndrome with autosomal dominant inheritance, involving germline mutations of the tumor suppressor gene. The most frequent tumors that arise in patients under the age of 45 are osteosarcomas, soft-tissue sarcomas, breast tumors in young women, leukemias/lymphomas, brain tumors, and tumors of the adrenal cortex. To date, no other gene mutations have been associated with LFS. The diagnosis is usually confirmed by genetic testing for the identification of mutations; therefore, these mutations are considered the biomarkers associated with the tumor spectrum of LFS. Here, we aim to review novel molecular mechanisms involved in the oncogenic functions of mutant p53 in LFS and to discuss recent new diagnostic and therapeutic approaches exploiting mutations as biomarkers and druggable targets.
PubMed: 35954327
DOI: 10.3390/cancers14153664 -
Frontiers in Endocrinology 2022Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old. It is primarily associated with Li-Fraumeni and Beckwith-Wiedemann tumor predisposition syndromes in children. The incidence of pediatric ACC is 10-15fold higher in southern Brazil due to a higher prevalence of mutation associated with Li-Fraumeni syndrome in that population. Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.
Topics: Adult; Humans; Child; Young Adult; Adrenocortical Carcinoma; Mitotane; Adrenal Cortex Neoplasms; Li-Fraumeni Syndrome
PubMed: 36387865
DOI: 10.3389/fendo.2022.961650 -
Journal of Medical Genetics Jun 2010BACKGROUND Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour...
TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes.
BACKGROUND Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria are in use to decide which patients qualify for TP53 mutation analysis, including the LFS, Li-Fraumeni-like (LFL) and Chompret criteria. We investigated which criteria for TP53 mutation analysis resulted in the highest mutation detection rate and sensitivity in Dutch families. We describe the tumour spectrum in TP53-positive families and calculated tumour type specific relative risks. METHOD A total of 180 Dutch families referred for TP53 mutation analysis were evaluated. Tumour phenotypes were verified by pathology reports or clinical records. RESULTS A TP53 germline mutation was identified in 24 families. When the Chompret criteria were used 22/24 mutations were detected (sensitivity 92%, mutation detection rate 21%). In LFS and LFL families 18/24 mutations were found (sensitivity 75%). The two mutations detected outside the 'Chompret group' were found in a child with rhabdomyosarcoma and a young woman with breast cancer. In the mutation carriers, in addition to the classical LFS tumour types, colon and pancreatic cancer were also found significantly more often than in the general population. CONCLUSION We suggest TP53 mutation testing for all families fulfilling the Chompret criteria. In addition, TP53 mutation testing can be considered in the event of childhood sarcoma and breast cancer before 30 years. In addition to the risk for established LFS tumour types, TP53-positive individuals may also have an elevated risk for pancreatic and colon cancer.
Topics: Adult; Colonic Neoplasms; DNA Mutational Analysis; Family Health; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Genotype; Germ-Line Mutation; Humans; Li-Fraumeni Syndrome; Male; Middle Aged; Neoplasms; Netherlands; Pancreatic Neoplasms; Phenotype; Risk Factors; Tumor Suppressor Protein p53; Young Adult
PubMed: 20522432
DOI: 10.1136/jmg.2009.073429 -
Cancer Discovery Jan 2024People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely...
UNLABELLED
People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 LFS patients. Multimodal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis and was able to detect cancer-associated signal(s) in carriers prior to diagnosis with conventional screening (positive predictive value = 67.6%, negative predictive value = 96.5%). Although adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with LFS.
SIGNIFICANCE
By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5.
Topics: Humans; Li-Fraumeni Syndrome; Tumor Suppressor Protein p53; Early Detection of Cancer; Cell-Free Nucleic Acids; Genes, p53; Germ-Line Mutation; Genetic Predisposition to Disease
PubMed: 37874259
DOI: 10.1158/2159-8290.CD-23-0456 -
Cold Spring Harbor Perspectives in... Jan 2010Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome,... (Review)
Review
Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. Most mutations are single-base substitutions distributed throughout the coding sequence. Their diverse types and positions may inform on the nature of mutagenic mechanisms involved in cancer etiology. TP53 mutations are also potential prognostic and predictive markers, as well as targets for pharmacological intervention. All mutations found in human cancers are compiled in the IARC TP53 Database (http://www-p53.iarc.fr/). A human TP53 knockin mouse model (Hupki mouse) provides an experimental model to study mutagenesis in the context of a human TP53 sequence. Here, we summarize current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge.
Topics: Animals; Carcinogens; CpG Islands; Gene Expression Regulation, Neoplastic; Genes, p53; Humans; Mice; Mice, Transgenic; Models, Biological; Mutagenesis; Mutation; Neoplasms; Prognosis
PubMed: 20182602
DOI: 10.1101/cshperspect.a001008 -
European Journal of Human Genetics :... Oct 2020Fifty years after the recognition of the Li-Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i)...
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.
Topics: Early Detection of Cancer; Genetic Testing; Humans; Li-Fraumeni Syndrome; Polymorphism, Genetic; Practice Guidelines as Topic; Tumor Suppressor Protein p53
PubMed: 32457520
DOI: 10.1038/s41431-020-0638-4 -
Human Mutation Mar 2021Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated...
Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a 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 is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. 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 developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared 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.
Topics: Genetic Testing; Genetic Variation; Germ Cells; Humans; Li-Fraumeni Syndrome; Tumor Suppressor Protein p53; United States
PubMed: 33300245
DOI: 10.1002/humu.24152