Beyond Li Fraumeni Syndrome: Clinical Characteristics of Families With p53 Germline Mutations

City of Hope National Medical Center, Дуарте, California, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 03/2009; 27(8):1250-6. DOI: 10.1200/JCO.2008.16.6959
Source: PubMed


A clinical testing cohort was used to gain a broader understanding of the spectrum of tumors associated with germline p53 mutations to aid clinicians in identifying high-risk families.
Full sequencing of the coding exons (2 to 11) and associated splice junctions of the p53 gene was performed on 525 consecutive patients whose blood samples were submitted for diagnostic testing. Clinical features of p53 germline carriers in this cohort were characterized, clinical referral schemes based on reported p53-associated family phenotypes were evaluated, and practical mutation prevalence tables were generated.
Mutations were identified in 91 (17%) of 525 patients submitted for testing. All families with a p53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma (ACC). Every individual with a choroid plexus tumor (eight of eight) and 14 of 21 individuals with a childhood ACC had a mutation regardless of family history. Based on reported personal and family history, 95% of patients (71 of 75) with a mutation met either classic Li Fraumeni syndrome (LFS) or Chompret criteria. A simplified prevalence table provides a concise summary of individual and family characteristics associated with p53 mutations.
This is, to our knowledge, the largest single report of diagnostic testing for germline p53 mutations, yielding practical mutation prevalence tables and suggesting clinical utility of classic LFS and Chompret criteria for identifying a subset of cancer-prone families with p53 germline mutations, with important implications for diagnosis and management.

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    • "P 53 germline mutations 2015 Brazilian Conference on Intelligent Systems 978-1-5090-0016-6/15 $31.00 © 2015 IEEE DOI 10.1109/BRACIS.2015.41 TABLE I. SUMMARY OF SPECIFICITY AND SENSITIVITY OF EACH LI-FRAUMENI CRITERIA, ADAPTED FROM [5] "
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    ABSTRACT: The computer-assisted search for knowledge in the medical field has become increasingly frequent. Scientific progress in subjects such as ontology and artificial intelligence allowed researchers to develop methods for capturing, using and sharing specific knowledge. The Li-Fraumeni Syndrome (LFS) is a syndrome that causes multiple primary tumors in children and young adults. These tumors can be Breast Cancer, Brain Tumors and Sarcomas, among others. This paper presents a case study of a new set of ontologies in the domain of the LFS with the objective of extracting knowledge about patients that fit clinical criteria of one or more of the four LFS clinical criteria: Classic, Birch, Eeles and Chompret.
    2015 Brazilian Conference on Intelligent Systems, Natal, RN, Brazil; 11/2015
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    • "Other risk factors for PNET/EWS include a possible genetic predisposition. Those individuals with Li-Fraumeni syndrome with germline p53 mutations have an increased risk for breast cancer and sarcoma [14]. One study of 525 patients, of which 91 were identified as having germline p53 mutations, showed a 35% incidence of breast cancer and a 26% incidence of sarcoma. "
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    ABSTRACT: Patient: Female, 51Final Diagnosis: Ewing sarcomaSymptoms: Visual disturbancesMedication: —Clinical Procedure: —Specialty: OncologyObjective:Rare diseaseBackground:Primitive neuroectodermal tumor/Ewing sarcoma (PNET/EWS) is a round blue cell sarcoma that shows varying degrees of neuroectodermal differentiation. PNET/EWS as a primary intracranial tumor is extremely uncommon.Case Report: We report a unique case of peripheral PNET presenting as an intracranial mass in an adult following chemotherapy and radiotherapy for a solid tumor. A 51-year-old woman with previously treated left breast cancer was evaluated for a newly developed brain mass. She underwent craniotomy with resection. Surgical pathology was consistent with a peripheral PNET/EWS with Ewing sarcoma gene translocation. She was treated appropriately with vincristine, cyclophosphamide, and doxorubicin (later dactinomycin) alternating with ifosfamide and etoposide.Conclusions:Although development of PNET/EWS presenting along the CNS is exceedingly rare in adults, establishing the proper diagnosis of this “small blue cell tumor” is critical. The further distinction between central PNET and peripheral PNET can greatly impact both prognosis and treatment. Our case also highlights the importance of considering the impact of prior intensive therapies, including radiation and chemotherapy, on predisposing to future PNET/EWS.
    American Journal of Case Reports 07/2014; 15:294-9. DOI:10.12659/AJCR.890656
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    • "LFS definitions and indications for TP53 testing are likely to continue to evolve as further evidence emerges to elucidate the role of germline TP53 mutations in different cancer types. For example , while leukemias were included among the original descriptions of LFS, subsequent studies suggested that leukemias may be a less common manifestation of germline TP53 mutations [Birch et al., 2001; Nichols et al., 2001; Gonzalez et al., 2009b]. However, emerging work now suggests that at least a certain subtype of pediatric acute lymphoblastic leukemia, low hypodiploid, is associated with germline TP53 mutations [Holmfeldt et al., 2013]. "
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    ABSTRACT: Since its description by Li and Fraumeni over 40 years ago, Li-Fraumeni syndrome (LFS) remains one of the most striking familial cancer predisposition syndromes. Children and adults are affected by a wide array of cancers that occur predominantly at younger ages. This review discusses LFS, describes its association with TP53, and examines the classic and evolving definitions of the syndrome. The potential implications of multi-gene assessments of individuals at increased cancer risk, which have already begun to identify individuals with very little personal or family cancer history carrying germline TP53 mutations, are considered. Newer options in the management of individuals with LFS are also discussed, highlighting the importance of further clinical trials for cancer detection, prevention and management. Finally, we observe how the clinical criteria for TP53 mutation screening appear to be evolving as our understanding of the impact of germline TP53 mutations continues to expand.This article is protected by copyright. All rights reserved
    Human Mutation 06/2014; 35(6). DOI:10.1002/humu.22559 · 5.14 Impact Factor
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