Amyloid-like p53 as prognostic biomarker in serous ovarian cancer—a study of the OVCAD consortium

TP53 is the most commonly mutated gene in cancer and has been shown to form amyloid-like aggregates, similar to key proteins in neurodegenerative diseases. Nonetheless, the clinical implications of p53 aggregation remain unclear. Here, we investigated the presence and clinical relevance of p53 aggre...

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Published in:	Oncogene Vol. 42; no. 33; pp. 2473 - 2484
Main Authors:	Heinzl, Nicole, Maritschnegg, Elisabeth, Koziel, Katarzyna, Schilhart-Wallisch, Christine, Heinze, Georg, Yang, Wei-Lei, Bast, Robert C., Sehouli, Jalid, Braicu, Elena I., Vergote, Ignace, Van Gorp, Toon, Mahner, Sven, Paspalj, Valentina, Grimm, Christoph, Obermayr, Eva, Schuster, Eva, Holzer, Barbara, Rousseau, Frederic, Schymkowitz, Joost, Concin, Nicole, Zeillinger, Robert
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 11.08.2023 Nature Publishing Group
Subjects:	13/1 13/2 13/51 14 14/63 45/29 631/67/1517/1709 692/53/2422 82 Amyloid Apoptosis Autoantibodies Cell Biology Cytotoxicity Human Genetics Immune response Internal Medicine Medical prognosis Medicine Medicine & Public Health Missense mutation Neurodegenerative diseases Oncology Ovarian cancer p53 Protein Survival
ISSN:	0950-9232, 1476-5594, 1476-5594
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Abstract	TP53 is the most commonly mutated gene in cancer and has been shown to form amyloid-like aggregates, similar to key proteins in neurodegenerative diseases. Nonetheless, the clinical implications of p53 aggregation remain unclear. Here, we investigated the presence and clinical relevance of p53 aggregates in serous ovarian cancer (OC). Using the p53-Seprion-ELISA, p53 aggregates were detected in 46 out of 81 patients, with a detection rate of 84.3% in patients with missense mutations. High p53 aggregation was associated with prolonged progression-free survival. We found associations of overall survival with p53 aggregates, but they did not reach statistical significance. Interestingly, p53 aggregation was significantly associated with elevated levels of p53 autoantibodies and increased apoptosis, suggesting that high levels of p53 aggregates may trigger an immune response and/or exert a cytotoxic effect. To conclude, for the first time, we demonstrated that p53 aggregates are an independent prognostic marker in serous OC. P53-targeted therapies based on the amount of these aggregates may improve the patient’s prognosis.
AbstractList	TP53 is the most commonly mutated gene in cancer and has been shown to form amyloid-like aggregates, similar to key proteins in neurodegenerative diseases. Nonetheless, the clinical implications of p53 aggregation remain unclear. Here, we investigated the presence and clinical relevance of p53 aggregates in serous ovarian cancer (OC). Using the p53-Seprion-ELISA, p53 aggregates were detected in 46 out of 81 patients, with a detection rate of 84.3% in patients with missense mutations. High p53 aggregation was associated with prolonged progression-free survival. We found associations of overall survival with p53 aggregates, but they did not reach statistical significance. Interestingly, p53 aggregation was significantly associated with elevated levels of p53 autoantibodies and increased apoptosis, suggesting that high levels of p53 aggregates may trigger an immune response and/or exert a cytotoxic effect. To conclude, for the first time, we demonstrated that p53 aggregates are an independent prognostic marker in serous OC. P53-targeted therapies based on the amount of these aggregates may improve the patient's prognosis.TP53 is the most commonly mutated gene in cancer and has been shown to form amyloid-like aggregates, similar to key proteins in neurodegenerative diseases. Nonetheless, the clinical implications of p53 aggregation remain unclear. Here, we investigated the presence and clinical relevance of p53 aggregates in serous ovarian cancer (OC). Using the p53-Seprion-ELISA, p53 aggregates were detected in 46 out of 81 patients, with a detection rate of 84.3% in patients with missense mutations. High p53 aggregation was associated with prolonged progression-free survival. We found associations of overall survival with p53 aggregates, but they did not reach statistical significance. Interestingly, p53 aggregation was significantly associated with elevated levels of p53 autoantibodies and increased apoptosis, suggesting that high levels of p53 aggregates may trigger an immune response and/or exert a cytotoxic effect. To conclude, for the first time, we demonstrated that p53 aggregates are an independent prognostic marker in serous OC. P53-targeted therapies based on the amount of these aggregates may improve the patient's prognosis. TP53 is the most commonly mutated gene in cancer and has been shown to form amyloid-like aggregates, similar to key proteins in neurodegenerative diseases. Nonetheless, the clinical implications of p53 aggregation remain unclear. Here, we investigated the presence and clinical relevance of p53 aggregates in serous ovarian cancer (OC). Using the p53-Seprion-ELISA, p53 aggregates were detected in 46 out of 81 patients, with a detection rate of 84.3% in patients with missense mutations. High p53 aggregation was associated with prolonged progression-free survival. We found associations of overall survival with p53 aggregates, but they did not reach statistical significance. Interestingly, p53 aggregation was significantly associated with elevated levels of p53 autoantibodies and increased apoptosis, suggesting that high levels of p53 aggregates may trigger an immune response and/or exert a cytotoxic effect. To conclude, for the first time, we demonstrated that p53 aggregates are an independent prognostic marker in serous OC. P53-targeted therapies based on the amount of these aggregates may improve the patient’s prognosis. TP53 is the most commonly mutated gene in cancer and has been shown to form amyloid-like aggregates, similar to key proteins in neurodegenerative diseases. Nonetheless, the clinical implications of p53 aggregation remain unclear. Here, we investigated the presence and clinical relevance of p53 aggregates in serous ovarian cancer (OC). Using the p53-Seprion-ELISA, p53 aggregates were detected in 46 out of 81 patients, with a detection rate of 84.3% in patients with missense mutations. High p53 aggregation was associated with prolonged progression-free survival. We found associations of overall survival with p53 aggregates, but they did not reach statistical significance. Interestingly, p53 aggregation was significantly associated with elevated levels of p53 autoantibodies and increased apoptosis, suggesting that high levels of p53 aggregates may trigger an immune response and/or exert a cytotoxic effect. To conclude, for the first time, we demonstrated that p53 aggregates are an independent prognostic marker in serous OC. P53-targeted therapies based on the amount of these aggregates may improve the patient’s prognosis.
Author	Heinze, Georg Yang, Wei-Lei Sehouli, Jalid Obermayr, Eva Vergote, Ignace Zeillinger, Robert Van Gorp, Toon Bast, Robert C. Schymkowitz, Joost Concin, Nicole Paspalj, Valentina Maritschnegg, Elisabeth Koziel, Katarzyna Braicu, Elena I. Rousseau, Frederic Grimm, Christoph Heinzl, Nicole Schuster, Eva Holzer, Barbara Mahner, Sven Schilhart-Wallisch, Christine
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Holzer fullname: Holzer, Barbara organization: Department of Obstetrics and Gynaecology, Molecular Oncology Group, Comprehensive Cancer Center-Gynaecologic Cancer Unit, Medical University of Vienna – sequence: 18 givenname: Frederic orcidid: 0000-0002-9189-7399 surname: Rousseau fullname: Rousseau, Frederic organization: Switch Laboratory, VIB-KU Leuven Center for Brain and Disease Research, Department of Cellular and Molecular Medicine, KU Leuven – sequence: 19 givenname: Joost surname: Schymkowitz fullname: Schymkowitz, Joost organization: Switch Laboratory, VIB-KU Leuven Center for Brain and Disease Research, Department of Cellular and Molecular Medicine, KU Leuven – sequence: 20 givenname: Nicole surname: Concin fullname: Concin, Nicole organization: Department of Gynaecology and Obstetrics, Innsbruck Medical University – sequence: 21 givenname: Robert orcidid: 0000-0001-6771-4591 surname: Zeillinger fullname: Zeillinger, Robert email: robert.zeillinger@meduniwien.ac.at organization: Department of Obstetrics and Gynaecology, Molecular Oncology Group, Comprehensive Cancer Center-Gynaecologic Cancer Unit, Medical University of Vienna
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Snippet	TP53 is the most commonly mutated gene in cancer and has been shown to form amyloid-like aggregates, similar to key proteins in neurodegenerative diseases.... TP53 is the most commonly mutated gene in cancer and has been shown to form amyloid-like aggregates, similar to key proteins in neurodegenerative diseases....
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SubjectTerms	13/1 13/2 13/51 14 14/63 45/29 631/67/1517/1709 692/53/2422 82 Amyloid Apoptosis Autoantibodies Cell Biology Cytotoxicity Human Genetics Immune response Internal Medicine Medical prognosis Medicine Medicine & Public Health Missense mutation Neurodegenerative diseases Oncology Ovarian cancer p53 Protein Survival
Title	Amyloid-like p53 as prognostic biomarker in serous ovarian cancer—a study of the OVCAD consortium
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