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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    • "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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    • "Since the introduction of classic LFS criteria [1], supplementary LFL criteria have been suggested [2, 3]. Chompret et al. [4-6] proposed modified criteria that demonstrated maximum clinical utility in combination with classic LFS [23]. However, approximately 4% of families harboring TP53 mutations are missed with the current criteria [23]. "
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    ABSTRACT: Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various early-onset tumors. Since the introduction of classic LFS criteria, various criteria have been proposed to include patients with incomplete LFS features, which make up Li-Fraumeni-like syndromes (LFL). Germline missense mutations of TP53 are the primary cause of LFS and LFL. Mutations mostly reside in the DNA-binding domain of the gene and have a dominant-negative effect (DNE) over alternate wild-type alleles. Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V) and has been reported in a case of multiple primary colon tumors. Herein we report a second case of the same mutation in a breast cancer patient, who has familial history of late-onset malignancies. Due to the relatively late onset of malignancies, neither case fulfils previously defined criteria for the syndrome. Mutational analysis for breast tissue in this patient showed a loss of heterozygosity. These clinical features may suggest a relatively weak DNE of A189V compared to other TP53 mutations, and in silico predictions and in vitro findings of the function of A189V mutant protein are conflicting. Considering the increased risk of malignancies and the therapeutic implications for patients who have a TP53 mutation, care must be taken when treating those who are suspected of possessing cancer-prone traits due to TP53 mutation, especially when there is a family history of late-onset cancer with low penetrance.
    Annals of Laboratory Medicine 05/2013; 33(3):212-6. DOI:10.3343/alm.2013.33.3.212 · 1.48 Impact Factor
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    • "TP53 is a tumour suppressor gene that causes Li-Fraumeni syndrome and affects adults and children. This highly penetrant gene predisposes for a wide spectrum of tumours, including sarcomas, adrenocortical carcinomas, brain cancer, and very early onset breast cancer [39, 40]. Most cancers are manifested from birth through late adulthood [39]. "
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    ABSTRACT: Breast cancer is the most common malignancy among females. 5%-10% of breast cancer cases are hereditary and are caused by pathogenic mutations in the considered reference BRCA1 and BRCA2 genes. As sequencing technologies evolve, more susceptible genes have been discovered and BRCA1 and BRCA2 predisposition seems to be only a part of the story. These new findings include rare germline mutations in other high penetrant genes, the most important of which include TP53 mutations in Li-Fraumeni syndrome, STK11 mutations in Peutz-Jeghers syndrome, and PTEN mutations in Cowden syndrome. Furthermore, more frequent, but less penetrant, mutations have been identified in families with breast cancer clustering, in moderate or low penetrant genes, such as CHEK2, ATM, PALB2, and BRIP1. This paper will summarize all current data on new findings in breast cancer susceptibility genes.
    03/2013; 2013(2):747318. DOI:10.1155/2013/747318
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