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David Malkin - One of the best experts on this subject based on the ideXlab platform.
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Abstract IA02: ModeLing sarcoma susceptibiLity: The Li-Fraumeni syndrome paradigm
Genomics, 2018Co-Authors: David MalkinAbstract:The original description of Li-Fraumeni syndrome (LFS) 1969 was generated from the ascertainment of medical and death records of over 600 children with rhabdomyosarcoma. Although the cLinical definition of LFS has evolved over the decades, the occurrence of sarcoma in at least one affected TP53 gene mutation carrier is common to many famiLies. However, the genotype:cancer phenotype association of sarcomas in mutation carriers remains poorly understood. This lecture will review some of the phenotypic characterizations of sarcomas in LFS and explore recent exciting advances that suggest a role for various genetic/genomic and epigenetic modifiers of the underlying germLine TP53 mutation in defining these cLinical phenotypes. The challenges and opportunities to enhance early tumor detection and modify disease risk will also be discussed. Citation Format: David Malkin. ModeLing sarcoma susceptibiLity: The Li-Fraumeni syndrome paradigm [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to CLinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; CLin Cancer Res 2018;24(2_Suppl):Abstract nr IA02.
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Li-Fraumeni Syndrome and p53 in 2015: Celebrating their Silver Anniversary.
Clinical and investigative medicine. Medecine clinique et experimentale, 2016Co-Authors: David MalkinAbstract:In a typical morning in the Cancer Genetics CLinic at The Hospital for Sick Children in Toronto, the following array of patients and famiLies might be seen: a family of three children, all harbouring a mutation of the succinyl dehydrogenase C gene inherited from their father who had had extensive surgery several years ago for a secreting paragangLioma; three famiLies with Li-Fraumeni syndrome, each with at least one child harbouring a TP53 gene mutation conferring a Lifetime risk of cancer approaching 100% and currently undergoing surveillance for early tumour detection; two children with Li-Fraumeni syndrome undergoing treatment for cancer - one having had three cancer diagnoses before 19 months of age and the other just completing therapy for metastatic adrenocortical carcinoma at age 3; two children with von Hippel-Lindau disease being monitored for persistent pancreatic neuroendocrine tumors and cerebellar hemangioblastomas, respectively; and one child with Beckwith-Wiedeman syndrome and Wilms tumor and another child completing therapy for a pleuropulmonary blastoma (PPB).
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Abstract 34: Investigating PIN1 as a genetic modifier in Li-Fraumeni syndrome
Poster Presentations, 2014Co-Authors: Anita Villani, Ana Novokmet, David MalkinAbstract:Background: Li-Fraumeni syndrome (LFS) is characterized by marked cLinical heterogeneity in site and age of cancer onset. The prolyl-isomerase, Pin1 (peptidylprolyl cis/trans isomerase, NIMA-interacting 1), has been shown to serve a fundamental role in mutant TP53 oncogenic gain of function and the promotion of aggressive cancer phenotypes. We sought to determine whether alterations in PIN1 modify the phenotype of patients with germLine mutations in TP53. Methods: The PIN1 promoter and coding regions were sequenced from peripheral blood lymphocyte samples of 107 individuals with Li-Fraumeni syndrome and documented TP53 mutations. The expression and activity levels of PIN1 were determined in paired patient-derived lymphoblastoid cell Lines. Results: Multivariate analysis of PIN1 variants with TP53 mutation status and selected cLinical parameters is in progress. A comprehensive summary of observed associations will be presented. Conclusions: Demonstration of a modifying effect of PIN1 on the cancer phenotype conferred by a germLine TP53 mutation may aid in the management of patients with Li-Fraumeni syndrome, including the implementation of patient-specific modifications of surveillance strategies for pre-symptomatic tumor detection. Citation Format: Anita Villani, Ana Novokmet, David Malkin. Investigating PIN1 as a genetic modifier in Li-Fraumeni syndrome. [abstract]. In: Proceedings of the AACR Special Conference: Cancer SusceptibiLity and Cancer SusceptibiLity Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 34. doi:10.1158/1538-7445.CANSUSC14-34
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Abstract IA10: Li-Fraumeni syndrome: p53 and beyond
Oral Presentations, 2014Co-Authors: Jonathan D. Wasserman, Anita Villani, Ana Novokmet, Nardin Samuel, Diana M. Merino, Margaret Pienkowska, Badr Idsaid, David MalkinAbstract:GermLine TP53 mutations are observed in ∼80% of patients with Li-Fraumeni syndrome (LFS) and a lesser frequency of patients meeting the revised Chompret criteria. A variety of studies are being conducted exploring the role of genetic modifiers on p53 function and their impact in refining the genotype:phenotype correlation of the TP53:LFS relationship. In this presentation, four classical pediatric-onset LFS tumors (choroid plexus carcinoma, medulloblastoma, adrenocortical carcinoma and rhabdomyosarcoma) will be used as examples to demonstrate the molecular nuances of this complex relationship. A spectrum of findings will be outLined that support the notion that presence of a germLine TP53 mutation in the context of different modifying effects of intragenic TP53 polymorphism as well as variants in genes and proteins that play important roles in the p53 network confers certain biological features to the presentation of these tumors. Biological mechanisms will be discussed and strategies for early cancer detection will be presented. Citation Format: Jonathan Wasserman, Anita Villani, Nardin Samuel, Diana Merino, Ana Novokmet, Margaret Pienkowska, Badr IdSaid, David Malkin. Li-Fraumeni syndrome: p53 and beyond. [abstract]. In: Proceedings of the AACR Special Conference: Cancer SusceptibiLity and Cancer SusceptibiLity Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA10. doi:10.1158/1538-7445.CANSUSC14-IA10
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Li-Fraumeni syndrome: Retesting archival DNA samples to identify previously unrecognized germ-Line p53 mutations.
Journal of Clinical Oncology, 2011Co-Authors: Ana Novokmet, Berivan Baskin, David MalkinAbstract:1520 Background: Li-Fraumeni syndrome (LFS) is a famiLial cancer predisposition syndrome that results from germLine alterations in the p53 gene. UnLike other cancer predisposition syndromes, LFS pr...
Holger Prokisch - One of the best experts on this subject based on the ideXlab platform.
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Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity
Breast cancer research : BCR, 2018Co-Authors: Judith Penkert, Gunnar Schmidt, Winfried Hofmann, Stephanie Schubert, Maximilian Schieck, Bernd Auber, Tim Ripperger, Karl Hackmann, Marc Sturm, Holger ProkischAbstract:Breast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-Like phenotype do not harbor detectable causative germLine TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilLing Li-Fraumeni(-Like) cLinical diagnostic criteria. To specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-Like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germLine variants. We identified 13 pathogenic or Likely pathogenic germLine variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in estabLished hereditary breast cancer susceptibiLity genes (i.e., PALB2, CHEK2, ATM). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibiLity to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14ARF, and RUNX1). Our study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoalleLic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-Like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-Like) syndrome lacking TP53 variants in coding regions.
Patricia Ashton-prolla - One of the best experts on this subject based on the ideXlab platform.
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Pediatric cancer and Li-Fraumeni/Li-Fraumeni-Like syndromes: a review for the pediatrician.
Revista da Associacao Medica Brasileira (1992), 2015Co-Authors: Cristina Rossi Giacomazzi, Juliana Giacomazzi, Cristina Brinckmann Oliveira Netto, Patricia Santos-silva, Simone Geiger De Almeida Selistre, Ana Luiza Silva Maia, Viviane Ziebell De Oliveira, Suzi Alves Camey, José Roberto Goldim, Patricia Ashton-prollaAbstract:Introduction: cancer is the second leading cause of death in children between the ages of 0 and 14 years, corresponding to approximately 3% of all cases diagnosed in Brazil. A significant percentage (5-10%) of pediatric cancers are associated with hereditary cancer syndromes, including Li-Fraumeni/Li-Fraumeni-Like syndromes (LFS/LFL), both of which are caused by TP53 germLine mutations. Recent studies have shown that a specific TP53 mutation, known as p.R337H, is present in 1 in 300 newborns in Southern and Southeast Brazil. In addition, a significant percentage of children with LFS/LFL spectrum tumors in the region have a family history compatible with LFS/LFL. Objective: to review cLinical relevant aspects of LFS/LFL by our multidiscipLinary team with focus on pediatric cancer. Methods: the NCBI (PubMed) and SciELO databases were consulted using the keywords Li-Fraumeni syndrome, Li-Fraumeni-Like syndrome and pediatric cancer; and all manuscripts pubLished between 1990 and 2014 using these keywords were retrieved and reviewed. Conclusion: although LFS/LFL is considered a rare disease, it appears to be substantially more common in certain geographic regions. Recognition of population- specific risks for the syndrome is important for adequate management of hereditary cancer patients and famiLies. In Southern and Southeastern Brazil, LFS/ LFL should be considered in the differential diagnosis of children with cancer, especially if within the spectrum of the syndrome. Due to the complexities of these syndromes, a multidiscipLinary approach should be sought for the counseLing, diagnosis and management of patients and famiLies affected by these disorders. Pediatricians and pediatric oncologists in areas with high prevalence of hereditary cancer syndromes have a central role in the recognition and proper referral of patients and famiLies to genetic cancer risk evaluation and management programs.
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Identification of a rare germ-Line variant in the TP53 3’UTR in individuals with the Li-Fraumeni-Like phenotype: A new mechanism of cancer predisposition?
Journal of Clinical Oncology, 2014Co-Authors: Gabriel De Souza Macedo, Maria Isabel Achatz, Karina Miranda Santiago, Juliana Giacomazzi, Igor Araújo Vieira, Vanessa Cortez-paixão, Patricia Ashton-prollaAbstract:11106 Background: Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-Like Syndrome (LFL), are inherited disorders characterized by increased predisposition to multiple early-onset cancers and are associate...
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The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-Like syndromes in BraziLian famiLies.
Cancer letters, 2006Co-Authors: Maria Isabel Achatz, Magali Olivier, Ghyslaine Martel-planche, Patricia Ashton-prolla, Florence Le Calvez, Ademar Lopes, Benedito Mauro Rossi, Roberto Giugliani, Edenir Inez Palmero, Fernando Regla VargasAbstract:A TP53 germLine mutation, R337H, has been previously described in children from southern Brazil with adrenocortical tumours but no documented famiLial history of other cancers. Here, we have screened for TP53 mutation 45 BraziLian unrelated individuals with family histories fulfilLing the cLinical definitions of Li-Fraumeni (LFS) or Li-Fraumeni-Like (LFL) syndromes. Mutations were found in 13 patients (28.9%), including six (46.1%) R337H mutations, and four novel germLine mutations (V173M, V197M, G244D and IVS6+1G>T). FamiLies with the R337H mutation presented a wide spectrum of tumours, including breast cancers (30.4%), brain cancers (10.7%), soft tissue sarcomas (10.7%) and adrenocortical carcinomas (8.9%). Testing of 53 BraziLian subjects with no cancer history showed that R337H was not a common polymorphism in that population. Moreover, loss of heterozygocity with retention of the R337H allele was observed in a breast adenocarcinoma, supporting a role for this mutation in breast tumorigenesis. These results show that the TP53 R337H germLine mutation predisposes to a larger spectrum of tumours, similar to the one reported for other TP53 mutations.
Rosalind A. Eeles - One of the best experts on this subject based on the ideXlab platform.
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Li Fraumeni syndrome cancer risk assessment and cLinical management
Nature Reviews Clinical Oncology, 2014Co-Authors: Kate A Mcbride, Rosalind A. Eeles, Mandy L Ballinger, Emma Killick, Judy Kirk, Martin H N Tattersall, David M Thomas, Gillian MitchellAbstract:Individuals with Li-Fraumeni syndrome, who carry germLine mutations in the TP53 gene that encodes the tumour-suppressor protein p53, are at high risk of developing cancers in multiple organs. In this Review, considerations for cancer screening and management in carriers of TP53 mutations are discussed, and an evidence-based approach to cancer surveillance in such individuals is proposed.
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Childhood predictive genetic testing for Li–Fraumeni syndrome
Familial cancer, 2009Co-Authors: D G R Evans, P. Lunt, Tara Clancy, Rosalind A. EelesAbstract:Presymptomatic genetic testing in childhood for adult onset conditions is generally discouraged as it does not directly benefit the child and removes their autonomy. In certain cancer prone conditions such as FamiLial Adenomatous Polyposis and Von Hippel Lindau disease there are risks of disease in childhood and benefit to children not inheriting a mutation in being able to forego unpleasant screening tests. Li-Fraumeni syndrome caused by constitutional TP53 mutations there are also impLications in childhood with a risk of around 20% of a childhood maLignancy. However, as yet no evidence based surveillance programme has been identified. We describe our experience of childhood testing for four children in two Li-Fraumeni famiLies caused by TP53 mutations.
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p53 therapy in a patient with Li-Fraumeni syndrome
Molecular cancer therapeutics, 2007Co-Authors: Neil Senzer, Jackie Nemunaitis, Michael Nemunaitis, Jeffrey P. Lamont, Martin Gore, Hani Gabra, Rosalind A. Eeles, Nayanta Sodha, Frank J. Lynch, Louis A. ZumsteinAbstract:Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome famiLies contain germ-Line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patient's tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these cLinical, radiographic, and molecular markers may prove useful in guiding future appLication of p53 tumor suppressor therapy.
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Li Fraumeni and related syndromes correlation between tumor type family structure and tp53 genotype
Cancer Research, 2003Co-Authors: Magali Olivier, Nayanta Sodha, Pierre Hainaut, David E Goldgar, Hiroko Ohgaki, Paul Kleihues, Rosalind A. EelesAbstract:A database has been created to collect information on famiLies carrying a germ-Line mutation in the TP53 gene and on famiLies affected with Li-Fraumeni syndromes [Li-Fraumeni syndrome (LFS) and Li-Fraumeni-Like syndrome (LFL)]. Data from the pubLished Literature have been included. The database is available onLine at http://www.iarc.fr/p53, as part of the IARC TP53 Database. The analysis of the 265 famiLies/individuals that have been included thus far has revealed several new findings. In classical LFS famiLies with a germ-Line TP53 mutation (83 famiLies), the mean age of onset of breast cancer was significantly lower than in LFS famiLies (16 famiLies) without a TP53 mutation (34.6 versus 42.5 years; P = 0.0035). In individuals with a TP53 mutation, a correlation between the genotype and phenotype was found. Brain tumors were associated with missense TP53 mutations located in the DNA-binding loop that contact the minor groove of DNA (P = 0.01), whereas adrenal gland carcinomas were associated with missense mutations located in the loops opposing the protein-DNA contact surface (P = 0.003). Finally, mutations Likely to result in a null phenotype (absence of the protein or loss of function) were associated with earLier onset brain tumors (P = 0.004). These observations have cLinical impLications for genetic testing and tumor surveillance in LFS/LFL famiLies.
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Analysis of Li-Fraumeni syndrome and Li-Fraumeni-Like famiLies for germLine mutations in Bcl10.
Cancer letters, 1999Co-Authors: J G Stone, Rosalind A. Eeles, Nayanta Sodha, V Murday, E Sheriden, R S HoulstonAbstract:The Li-Fraumeni syndrome (LFS) is a dominant disease whose hallmark is an increased risk of breast cancers, brain tumours, sarcomas, leukaemia and adrenal carcinoma. Some, but not all LFS and Li-Fraumeni-Like (LFL) famiLies are caused by TP53 mutations. Bcl10 is a recently identified tumour suppressor reported to be commonly mutated in a wide range of cancers. To investigate the possibiLity that Bcl10 is a susceptibiLity gene for LFS and LFL we have analysed 27 LFS/LFL famiLies. No mutations were observed. This indicates that Bcl10 is unLikely to act as a susceptibiLity gene for LFS and LFL.
Judith Penkert - One of the best experts on this subject based on the ideXlab platform.
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Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity
Breast cancer research : BCR, 2018Co-Authors: Judith Penkert, Gunnar Schmidt, Winfried Hofmann, Stephanie Schubert, Maximilian Schieck, Bernd Auber, Tim Ripperger, Karl Hackmann, Marc Sturm, Holger ProkischAbstract:Breast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-Like phenotype do not harbor detectable causative germLine TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilLing Li-Fraumeni(-Like) cLinical diagnostic criteria. To specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-Like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germLine variants. We identified 13 pathogenic or Likely pathogenic germLine variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in estabLished hereditary breast cancer susceptibiLity genes (i.e., PALB2, CHEK2, ATM). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibiLity to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14ARF, and RUNX1). Our study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoalleLic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-Like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-Like) syndrome lacking TP53 variants in coding regions.