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A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer.

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.

SUBMITTER: Cho Y

PROVIDER: S-EPMC3646199 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer.

Cho Yonggeun Y Kim Juwon J Kim Yoonjung Y Jeong Joon J Lee Kyung-A KA

Annals of laboratory medicine 20130417 3

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-t ...[more]

PMID: 23667851

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Project description:BackgroundLi-Fraumeni Syndrome (LFS) is a rare disease with autosomal dominant inheritance linked to germline mutations of tumor suppressor gene TP53. These patients are predisposed to malignancies such as sarcoma, breast cancer, leukemia, and other malignancies. Breast cancer, the most common malignancy in adult patients with LFS, has an early-onset presentation and is usually treated as per the guidelines for the general population due to the limited literature about breast cancer in LFS. We aimed to describe our institutional experience treating patients with breast cancer and LFS to contribute to literature about this entity.DesignRetrospective single-institution case-series study. We searched for cases with LFS and breast cancer from 01/01/2000 to 12/31/2015 with treatment received at our institution.ResultsWe identified 4 cases (2 African Americans, 1 Indian, and 1 Hispanic) in 4 different families, who were diagnosed with LFS after presenting with breast cancer. Three cases were triple-negative disease and 1 case was ER+, HER2 positive disease. They were treated with mastectomy and a third-generation breast chemotherapy regimen and/or trastuzumab-containing regimen. Radiation therapy was used in 2 patients. Breast cancer recurrence was seen in 1 patient, while three other malignancies were identified after breast cancer treatment (1 breast sarcoma, 1 leiomyosarcoma, and 1 myelodysplastic syndrome). A patient, who underwent surveillance with a positron emission tomography-computed tomography scan, was found to have a stage I leiomyosarcoma and was treated with surgical resection, but then developed metastatic disease requiring cytotoxic chemotherapy.ConclusionBreast cancer among patients with LFS needs a multidisciplinary treatment approach. Surgical management follows the guidelines for the general population. Risk-benefit assessment of chemotherapy and radiotherapy needs to be performed carefully in a case-by-case approach. Patients should undergo multimodality cancer surveillance, preferably in the context of a clinical trial.

Project description:BackgroundBreast 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.MethodsTo 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.ResultsWe 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).ConclusionsOur 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.

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A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer.

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A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer.

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