Elsevier

Clinical Oncology

Volume 19, Issue 7, September 2007, Pages 490-493
Clinical Oncology

Original article
Rapid Development of Post-radiotherapy Sarcoma and Breast Cancer in a Patient with a Novel Germline ‘De-NovoTP53 Mutation

https://doi.org/10.1016/j.clon.2007.05.001Get rights and content

Abstract

Aims

Germline mutations in the TP53 tumour suppressor gene are associated with Li–Fraumeni syndrome, which is characterised by a spectrum of neoplasms occurring in children and young adults that predominantly include early-onset breast cancer, a variety of sarcomas, brain tumours and adrenocortical tumours. The identification of patients carrying TP53 mutations is primarily based on a positive family history of these early-onset characteristic cancer types. The aim of this study is to emphasize the importance of TP53 molecular testing in patients with very early onset breast cancer and no family history of cancer.

Materials and methods

A young woman with no family history of cancer presented with bilateral breast cancer at the age of 27 years. Forty months later she developed malignant fibrous histiocytoma of the right clavicle and another primary left breast cancer. Molecular testing of mutations 185delAG, 5382insC in BRCA1 gene and 6174delT in BRCA2 gene was performed using multiplex PCR and separation on a denaturing polyacrylamide gel. TP53 molecular analysis was performed by PCR-SSCP analysis of the whole coding region of the TP53. Exon 8 PCR products were sequenced using an ABI dye terminator kit and examined on an ABI 3100 automated sequencer.

Results

Molecular testing of peripheral blood DNA did not reveal mutations in BRCA1 or BRCA2 genes. A novel germline TP53 mutation, c.G841C, p.D281N, was identified. The detected mutation is a missense substitution, c.G841C, resulting in the substitution of the amino acid aspartate to asparagine, p.D281N. Molecular analysis in her parents showed that neither of them carried the mutation.

Conclusions

We describe a novel ‘de novoTP53 mutation and discuss the importance of molecular testing in early-onset breast cancer patients and its effect on the management and outcome of the disease.

Introduction

Li–Fraumeni syndrome (LFS) is a rare autosomal dominant familial cancer disorder characterised by the diagnosis of bone or soft tissue sarcoma under the age of 45 years, in an individual from a family with a first-degree relative with any cancer under 45 years of age and a first- or second-degree relative with any cancer under 45 years of age or a sarcoma at any age [1]. In most LFS families, a germline mutation is found in the tumour suppressor gene TP53[2], a transcription factor, implicated in a variety of cellular processes, including cellular regulation of DNA repair and programmed cell death 3, 4. It facilitates these functions by regulating the expression of several genes. This p53-regulated gene expression depends on the sequence-specific binding of p53 to DNA of other genes, conformation, post-translational modifications and levels of p53 among other parameters [5]. Inactivation of p53 regulation is a common step in the development of various tumours and somatic p53 mutations are associated with nearly one-half of human cancers.

The role of TP53 in ionising radiation stress responses is well described [6]. Lymphocytes from individuals carrying a germline TP53 mutation have been found to show a reduced apoptotic response after exposure to γ-radiation [7]. It has been suggested that exposure to radiation could induce a high incidence of secondary malignancies among carriers of a TP53 mutation [8]. Malignant fibrous histiocytoma (MFH) among other sarcomas are reported to erupt as secondary malignancy after irradiation. The median time between the exposure to irradiation and the appearance of the sarcoma can be as long as 16 years [9]. Breast cancers are also reported as secondary tumours, erupting after radiation with a median latency period of over 20 years.

Here we describe a patient harbouring a novel de novo TP53 mutation who was initially treated for bilateral breast cancer and 40 months later developed MFH of the right clavicle located in the irradiation field and a third primary right breast cancer. We also discuss the place of genetic testing in individuals with early-onset breast cancer without a significant family history.

Section snippets

Case Report

The patient, a woman of Jewish extended Ashkenazi origin, presented at the age of 27 years with bilateral breast cancer. An extensive pedigree was obtained. There was no history of malignancy in her family. She underwent left mastectomy and right lumpectomy and was diagnosed with left stage II (T2 N1 M0) grade 3 invasive ductal carcinoma and right clinical stage I (T1 Nx M0) grade 3 invasive ductal carcinoma, which were both oestrogen receptor positive. The patient was treated with adjuvant

Discussion

We describe the case of a young woman with no history of cancer in her family, presenting with bilateral primary breast cancers followed by the development of a new medullary breast cancer and MFH in the irradiation field, 3.5 years post-treatment. Molecular testing revealed a novel germline TP53 mutation, c.G841C, p.D281N. Intriguingly, the TP53 mutation, detected in the young patient, was not found in any of her parents. Thus, the TP53 alteration could be due to a de novo germline mutation

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A. Salmon and D. Amikam are joint first authors.

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