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Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome

BACKGROUND: Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder characterized by germline mutations of the p53 tumor-suppressor gene. In response to DNA damage, p53 stimulates protective cellular processes including cell-cycle arrest and apoptosis to prevent aberrant cell proliferation. C...

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Autores principales: Schuler, Nadine, Palm, Jan, Schmitz, Sabine, Lorat, Yvonne, Rübe, Claudia E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862648/
https://www.ncbi.nlm.nih.gov/pubmed/29594232
http://dx.doi.org/10.1016/j.ctro.2017.10.004
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author Schuler, Nadine
Palm, Jan
Schmitz, Sabine
Lorat, Yvonne
Rübe, Claudia E.
author_facet Schuler, Nadine
Palm, Jan
Schmitz, Sabine
Lorat, Yvonne
Rübe, Claudia E.
author_sort Schuler, Nadine
collection PubMed
description BACKGROUND: Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder characterized by germline mutations of the p53 tumor-suppressor gene. In response to DNA damage, p53 stimulates protective cellular processes including cell-cycle arrest and apoptosis to prevent aberrant cell proliferation. Current cancer therapies involve agents that damage DNA, which also affect non-cancerous hematopoietic stem/progenitor cells. Here, we report on a child with LFS who developed genomic instability during craniospinal irradiation for metastatic choroid plexus carcinoma (CPC). CASE PRESENTATION: This previously healthy 4-year-old boy presented with parieto-temporal brain tumor, diagnosed as CPC grade-3. Screening for cancer-predisposing syndrome revealed heterozygous p53 germline mutation, leading to LFS diagnosis. After tumour resection and systemic chemotherapy, entire craniospinal axis was irradiated due to leptomeningeal seeding, resulting in disease stabilization for nearly 12 months. Blood lymphocytes of LFS patient (p53-deficient) and age-matched tumor-children (p53-proficient) were collected before, during and after craniospinal irradiation and compared with asymptomatic carriers for identical p53 mutation, not exposed to DNA-damaging treatment. In p53-deficient lymphocytes of LFS patient radiation-induced DNA damage failed to induce cell-cycle arrest or apoptosis. Although DNA repair capacity was not impaired, p53-deficient blood lymphocytes of LFS patient showed significant accumulation of 53BP1-foci during and even several months after irradiation, reflecting persistent DNA damage. Electron microscopy revealed DNA abnormalities ranging from simple unrepaired lesions to chromosomal abnormalities. Metaphase spreads of p53-deficient lymphocytes explored by mFISH revealed high amounts of complex chromosomal aberrations after craniospinal irradiation. CONCLUSIONS: Tumor suppressor p53 plays a central role in maintaining genomic stability by promoting cell-cycle checkpoints and apoptosis. Here, we demonstrate that a patient with LFS receiving craniospinal irradiation including large volumes of bone marrow developed progressive genomic instability of the hematopoietic system. During DNA-damaging radiotherapy, genome-stabilizing mechanisms in proliferating stem/progenitor cells are perturbed by p53 deficiency, increasing the risk of cancer initiation and progression.
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spelling pubmed-58626482018-03-28 Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome Schuler, Nadine Palm, Jan Schmitz, Sabine Lorat, Yvonne Rübe, Claudia E. Clin Transl Radiat Oncol Article BACKGROUND: Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder characterized by germline mutations of the p53 tumor-suppressor gene. In response to DNA damage, p53 stimulates protective cellular processes including cell-cycle arrest and apoptosis to prevent aberrant cell proliferation. Current cancer therapies involve agents that damage DNA, which also affect non-cancerous hematopoietic stem/progenitor cells. Here, we report on a child with LFS who developed genomic instability during craniospinal irradiation for metastatic choroid plexus carcinoma (CPC). CASE PRESENTATION: This previously healthy 4-year-old boy presented with parieto-temporal brain tumor, diagnosed as CPC grade-3. Screening for cancer-predisposing syndrome revealed heterozygous p53 germline mutation, leading to LFS diagnosis. After tumour resection and systemic chemotherapy, entire craniospinal axis was irradiated due to leptomeningeal seeding, resulting in disease stabilization for nearly 12 months. Blood lymphocytes of LFS patient (p53-deficient) and age-matched tumor-children (p53-proficient) were collected before, during and after craniospinal irradiation and compared with asymptomatic carriers for identical p53 mutation, not exposed to DNA-damaging treatment. In p53-deficient lymphocytes of LFS patient radiation-induced DNA damage failed to induce cell-cycle arrest or apoptosis. Although DNA repair capacity was not impaired, p53-deficient blood lymphocytes of LFS patient showed significant accumulation of 53BP1-foci during and even several months after irradiation, reflecting persistent DNA damage. Electron microscopy revealed DNA abnormalities ranging from simple unrepaired lesions to chromosomal abnormalities. Metaphase spreads of p53-deficient lymphocytes explored by mFISH revealed high amounts of complex chromosomal aberrations after craniospinal irradiation. CONCLUSIONS: Tumor suppressor p53 plays a central role in maintaining genomic stability by promoting cell-cycle checkpoints and apoptosis. Here, we demonstrate that a patient with LFS receiving craniospinal irradiation including large volumes of bone marrow developed progressive genomic instability of the hematopoietic system. During DNA-damaging radiotherapy, genome-stabilizing mechanisms in proliferating stem/progenitor cells are perturbed by p53 deficiency, increasing the risk of cancer initiation and progression. Elsevier 2017-11-02 /pmc/articles/PMC5862648/ /pubmed/29594232 http://dx.doi.org/10.1016/j.ctro.2017.10.004 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Schuler, Nadine
Palm, Jan
Schmitz, Sabine
Lorat, Yvonne
Rübe, Claudia E.
Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome
title Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome
title_full Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome
title_fullStr Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome
title_full_unstemmed Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome
title_short Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome
title_sort increasing genomic instability during cancer therapy in a patient with li-fraumeni syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862648/
https://www.ncbi.nlm.nih.gov/pubmed/29594232
http://dx.doi.org/10.1016/j.ctro.2017.10.004
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