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David Malkin - One of the best experts on this subject based on the ideXlab platform.

  • Management of orbital rhabdomyosarcoma in a child with Li-Fraumeni Syndrome.
    Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 2019
    Co-Authors: Imran Jivraj, David Malkin, Gino R. Somers, Michel J. Belliveau, Dan D. Deangelis
    Abstract:

    This case highlights the management of orbital rhabdomyosarcoma in a child with Li Fraumeni Syndrome (LFS). Treatment with chemotherapy and eventual orbital exenteration enabled margin-free control of the tumor. Radiation therapy was avoided to reduce the risk of inducing additional malignancy. Reactive orbital hyperostosis was observed postoperatively and was confirmed with surgical biopsy of the orbital roof. In this case, systemic surveillance imaging, which is necessary in patients with LFS, revealed an adrenal cortical carcinoma.

  • Abstract IA02: Modeling sarcoma susceptibility: The Li-Fraumeni Syndrome paradigm
    Genomics, 2018
    Co-Authors: David Malkin
    Abstract:

    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.

  • Inherited TP53 Mutations and the Li-Fraumeni Syndrome.
    Cold Spring Harbor perspectives in medicine, 2017
    Co-Authors: Tanya Guha, David Malkin
    Abstract:

    Li-Fraumeni Syndrome (LFS) is a complex hereditary cancer predisposition disorder associated with early-onset cancers in diverse tissues of origin. Germline TP53 mutations are identified in 75% of patients with classic LFS. The lifetime likelihood of a TP53 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 TP53 mutations is anticipated to shed light on this intriguing, yet devastating, disease and to transform the clinical management of patients.

  • Li-Fraumeni Syndrome and p53 in 2015: Celebrating their Silver Anniversary.
    Clinical and investigative medicine. Medecine clinique et experimentale, 2016
    Co-Authors: David Malkin
    Abstract:

    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).

  • Abstract 34: Investigating PIN1 as a genetic modifier in Li-Fraumeni Syndrome
    Poster Presentations, 2014
    Co-Authors: Anita Villani, Ana Novokmet, David Malkin
    Abstract:

    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

Rosalind A. Eeles - One of the best experts on this subject based on the ideXlab platform.

  • li fraumeni Syndrome cancer risk assessment and clinical management
    Nature Reviews Clinical Oncology, 2014
    Co-Authors: Kate A Mcbride, Rosalind A. Eeles, Mandy L Ballinger, Emma Killick, Judy Kirk, Martin H N Tattersall, David M Thomas, Gillian Mitchell
    Abstract:

    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.

  • Childhood predictive genetic testing for Li–Fraumeni Syndrome
    Familial cancer, 2009
    Co-Authors: D G R Evans, P. Lunt, Tara Clancy, Rosalind A. Eeles
    Abstract:

    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.

  • p53 therapy in a patient with Li-Fraumeni Syndrome
    Molecular cancer therapeutics, 2007
    Co-Authors: Neil Senzer, Jackie Nemunaitis, Michael Nemunaitis, Jeffrey P. Lamont, Martin Gore, Hani Gabra, Rosalind A. Eeles, Nayanta Sodha, Frank J. Lynch, Louis A. Zumstein
    Abstract:

    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.

Charles D. Stiles - One of the best experts on this subject based on the ideXlab platform.

  • Expression of platelet derived growth factor and platelet derived growth factor receptor mRNA in a glioblastoma from a patient with Li-Fraumeni Syndrome.
    Journal of neurology neurosurgery and psychiatry, 1995
    Co-Authors: Abhijit Guha, Danuta Glowacka, Rona S. Carroll, Kathleen Dashner, Peter Mcl. Black, Charles D. Stiles
    Abstract:

    Expression of platelet derived growth factor (PDGF) and PDGF-receptor mRNA was examined from a glioblastoma taken from a patient with Li-Fraumeni Syndrome. Northern blot analysis and in situ hybridisation showed very high concentrations of both PDGF-A and PDGF alpha-receptor mRNA in the tumour. The overall pattern of PDGF expression was similar to those found in sporadic glioblastomas. Mutations in p53 has been implicated as an early pathogenic event leading to sporadic low grade astrocytomas, and is the third most common tumour type in patients with Li-Fraumeni Syndrome, where they are predisposed due to a germline mutation in the p53 tumour suppressor gene. This study suggests that progression towards a glioblastoma in both the general population and in patients with Li-Fraumeni Syndrome may involve potential autocrine and paracrine stimulation by growth factors such as PDGF.

Joseph F. Fraumeni - One of the best experts on this subject based on the ideXlab platform.

  • Novel p53 splice site mutations in three families with Li-Fraumeni Syndrome.
    Oncogene, 2000
    Co-Authors: Sigitas Verselis, Joseph F. Fraumeni, James G. Rheinwald, Frederick P. Li
    Abstract:

    Germline mutations in the p53 tumor suppressor gene predispose to a variety of cancers in families with Li-Fraumeni Syndrome. Most germline p53 mutations observed to date cause amino acid substitutions in the protein's central sequence-specific DNA binding domain. Outside this conserved core region, however, we found novel alterations in sequences that regulate precursor mRNA splicing in three Li-Fraumeni Syndrome families. Two splice site mutations affected the consensus sequence at the splice donor sites of introns 1 and 9, and produced unstable variant transcripts in normal cells. A third mutation at the splice acceptor site of intron 9 generated splicing at a cryptic acceptor site in intron 9. These splice site alterations emphasize the need to examine both noncoding and untranslated regions of the p53 gene for germline mutations in Li-Fraumeni Syndrome families.

  • heterozygous germ line hchk2 mutations in li fraumeni Syndrome
    Science, 1999
    Co-Authors: Daphne W Bell, Sigitas Verselis, J M Varley, Tara E Szydlo, Deborah H Kang, Doke C R Wahrer, Kristen E Shannon, Marcie Lubratovich, Kurt J Isselbacher, Joseph F. Fraumeni
    Abstract:

    The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G2 checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni Syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene. These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and they also provide a link between the central role of p53 inactivation in human cancer and the well-defined G2 checkpoint in yeast.

  • Multiple Primary Cancers in Families With Li-Fraumeni Syndrome
    Journal of the National Cancer Institute, 1998
    Co-Authors: Michie Hisada, Judy Garber, Claire Y. Fung, Joseph F. Fraumeni
    Abstract:

    BACKGROUND Li-Fraumeni Syndrome is a dominantly inherited disorder characterized by early-onset breast cancer, sarcomas, and other cancers in children and young adults. Members of families with this Syndrome also develop multiple primary cancers, but the frequency is unknown. To approach this issue, we quantified the incidence of second and third primary cancers in individuals from 24 Li-Fraumeni kindreds originally diagnosed with cancer during the period from 1968 through 1986. METHODS The relative risk (RR) of subsequent cancers and 95% confidence intervals (CIs) were calculated by use of population-based incidence data from the Connecticut Cancer Registry. Kaplan-Meier analysis was used to determine the cumulative probability (+/- standard error) of subsequent cancers. RESULTS Among 200 Li-Fraumeni Syndrome family members diagnosed with cancer, 30 (15%) developed a second cancer. Eight individuals (4%) had a third cancer, while four (2%) eventually developed a fourth cancer. Overall, the RR of occurrence of a second cancer was 5.3 (95% CI = 2.8-7.8), with a cumulative probability of second cancer occurrence of 57% (+/- 10%) at 30 years after diagnosis of a first cancer. RRs of second cancers occurring in families with this Syndrome were 83.0 (95% CI = 36.9-187.6), 9.7 (95% CI = 4.9-19.2), and 1.5 (95% CI = 0.5-4.2) for individuals with a first cancer at ages 0-19 years, 20-44 years, and 45 years or more, respectively. Thirty (71%) of 42 subsequent cancers in this group were component cancers of Li-Fraumeni Syndrome. CONCLUSIONS Compared with the general population, members of Li-Fraumeni Syndrome families have an exceptionally high risk of developing multiple primary cancers. The excess risk of additional primary cancers is mainly for cancers that are characteristic of Li-Fraumeni Syndrome, with the highest risk observed for survivors of childhood cancers. Cancer survivors in these families should be closely monitored for early manifestations of new cancers.

Maria Isabel Achatz - One of the best experts on this subject based on the ideXlab platform.

  • Molecular and clinical profile of Li-Fraumeni Syndrome in a Brazilian cohort.
    Journal of Clinical Oncology, 2015
    Co-Authors: Maria Nirvana Formiga, Amanda F. Nóbrega, Karina Miranda Santiago, Maria Isabel Achatz
    Abstract:

    e12533 Background: Li-Fraumeni Syndrome (LFS), an autosomal dominant highly penetrant cancer predisposition Syndrome, is associated with germline mutations in TP53 gene and characterized by a varie...

  • Analysis of global gene expression in adrenocortical tumors from Li-Fraumeni Syndrome TP53 germline mutation carriers.
    Journal of Clinical Oncology, 2014
    Co-Authors: Fernanda P. Fortes, Karina Miranda Santiago, Hellen Kuasne, Fabio Albuquerque Marchi, Silvia Regina Rogatto, Maria Isabel Achatz
    Abstract:

    1562 Background: Li Fraumeni Syndrome (LFS) is a rare autosomal dominant hereditary cancer Syndrome. In Brazil, a variant form of LFS is often due to a founder mutation p.R337H TP53. The occurrence...

  • Gastric cancer in individuals with Li-Fraumeni Syndrome
    Genetics in medicine : official journal of the American College of Medical Genetics, 2011
    Co-Authors: Serena Masciari, Akriti Dewanwala, Elena M. Stoffel, Gregory Y. Lauwers, Hui Zheng, Maria Isabel Achatz, Douglas L. Riegert-johnson, Lenka Foretova, Edaise M. Silva, Lisa Digianni
    Abstract:

    Purpose: Li-Fraumeni Syndrome is a rare hereditary cancer Syndrome associated with germline mutations in the TP53 gene. Although sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as Li-Fraumeni Syndrome-associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer in Li-Fraumeni Syndrome. Methods: Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute Li-Fraumeni Syndrome registry. We identified subjects with gastric cancer documented either by pathology report or death certificate and performed pathology review of the available specimens. Results: Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. Gastric cancer was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at gastric cancer diagnosis were 43 and 36 years, respectively (range: 24–74 years), significantly younger compared with the median age at diagnosis in the general population based on Surveillance Epidemiology and End Results data (71 years). Five (8.1%) families reported two or more cases of gastric cancer, and six (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies. Conclusions: Early-onset gastric cancer seems to be a component of Li-Fraumeni Syndrome, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of gastric cancer.

  • Tumor protein 53 mutations and inherited cancer: beyond Li-Fraumeni Syndrome.
    Current opinion in oncology, 2010
    Co-Authors: Edenir Inêz Palmero, Magali Olivier, Maria Isabel Achatz, Patricia Ashton-prolla, Pierre Hainaut
    Abstract:

    Purpose of review Germline TP53 (tumor protein 53) mutations are the molecular basis of a complex cancer predisposition Syndrome, the Li-Fraumeni Syndrome. The present review discusses the diversity of tumor patterns in TP53 mutation carriers, focusing on molecular factors that may explain familial and individual differences, such as genotype/phenotype correlations, genetic modifiers and genetic anticipation. Recent findings Initially identified 20 years ago, germline TP53 mutations appear to be associated with an extremely diverse range of cancers. Although no other gene has been found in Li-Fraumeni Syndrome, recent results show that the functional effects of particular mutations, polymorphisms in TP53 or in regulators such as MDM2 (murine double minute 2), variations in DNA copy number and variations in telomere length, have a strong impact on individual risk and on tumor patterns. Furthermore, recent studies in large cohorts suggest that TP53 germline mutations may occur in up to 1: 5000 individuals. Summary Germline TP53 mutations may be responsible for a large fraction (15-20%) of all inherited cancers. Although mutations are detectable by sequencing, counseling and follow-up remain problematic due to the wide variations in disease presentation. Elucidating the molecular mechanisms underlying the predisposition caused by TP53 deficiency may help to develop better, evidence-based and personalized clinical protocols.