Original articleRapid Development of Post-radiotherapy Sarcoma and Breast Cancer in a Patient with a Novel Germline ‘De-Novo’ TP53 Mutation
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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Cited by (68)
A systematic review exploring the role of modern radiation for the treatment of Hereditary or Familial Breast Cancer
2022, Radiotherapy and OncologyCitation Excerpt :Table 2 summarizes various case studies on pathogenic variants in TP53 gene in breast cancer patients. Though there is limited data regarding RT-induced toxicities or the rates of CBC in TP53 carriers, there is a considerable risk of secondary malignancies, as evident from specific case reports and series [41–44], which has reduced significantly over time [45,46]. PTEN, STK11, CDH1, and PALB2: PTEN gene (phosphatase and tensin homolog), CDH1 (Cadherin 1 gene), STK11 (serine/ threonine kinase 11 gene) and PALB2 (encoding a BRCA2-interacting protein) are crucial high-penetrance genes with breast cancer association (Table 3) [47].
Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations
2018, European Journal of CancerCitation Excerpt :In the French LFS series, we observed that 43% of the TP53 mutation carriers develop at least a second primary cancer [7], and this percentage was probably underestimated, as not every patient had benefited from an extensive follow-up. Furthermore, we observed that at least 30% of patients, who had received radiotherapy [7], developed a secondary tumour within the radiation field, confirming other previous observations [19–22]. Finally, we and others described the sequential development of tumours after treatment of a first cancer in TP53 mutation carriers who were tumour-free until 40 years of age [7,16].
In reply to Purushothaman et al
2015, International Journal of Radiation Oncology Biology PhysicsASTRO Radiation Therapy Summary of the ASCO-ASTRO-SSO Guideline on Management of Hereditary Breast Cancer
2020, Practical Radiation OncologyCitation Excerpt :There was, by contrast, just 1 event (CBC) among patients who had not received postoperative RT. Outcomes reported in published case reports support this recommendation against RT in women with breast cancer who are carriers of a TP53 mutation.27-31 The indications for and use of genetic testing are becoming more widespread in the multidisciplinary management of patients with breast cancer.
The construction and analysis of a prognostic assessment model based on P53-related multi-genes in breast carcinoma
2023, European Journal of Cancer Prevention
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A. Salmon and D. Amikam are joint first authors.