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Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients
BACKGROUND: PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gai...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366904/ https://www.ncbi.nlm.nih.gov/pubmed/25742468 http://dx.doi.org/10.1038/bjc.2015.79 |
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author | Zajkowicz, A Butkiewicz, D Drosik, A Giglok, M Suwiński, R Rusin, M |
author_facet | Zajkowicz, A Butkiewicz, D Drosik, A Giglok, M Suwiński, R Rusin, M |
author_sort | Zajkowicz, A |
collection | PubMed |
description | BACKGROUND: PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown. METHODS: The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays. RESULTS: The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes (BAX and MDM2). CONCLUSIONS: The truncating mutations of PPM1D are present in blood DNA of NSCLC patients at frequency similar to percentage determined for ovarian cancer patients. Our findings raise a question if the detected lesions are a result of chemotherapy. |
format | Online Article Text |
id | pubmed-4366904 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-43669042016-03-17 Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients Zajkowicz, A Butkiewicz, D Drosik, A Giglok, M Suwiński, R Rusin, M Br J Cancer Genetics and Genomics BACKGROUND: PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown. METHODS: The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays. RESULTS: The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes (BAX and MDM2). CONCLUSIONS: The truncating mutations of PPM1D are present in blood DNA of NSCLC patients at frequency similar to percentage determined for ovarian cancer patients. Our findings raise a question if the detected lesions are a result of chemotherapy. Nature Publishing Group 2015-03-17 2015-03-05 /pmc/articles/PMC4366904/ /pubmed/25742468 http://dx.doi.org/10.1038/bjc.2015.79 Text en Copyright © 2015 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/4.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
spellingShingle | Genetics and Genomics Zajkowicz, A Butkiewicz, D Drosik, A Giglok, M Suwiński, R Rusin, M Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients |
title | Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients |
title_full | Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients |
title_fullStr | Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients |
title_full_unstemmed | Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients |
title_short | Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients |
title_sort | truncating mutations of ppm1d are found in blood dna samples of lung cancer patients |
topic | Genetics and Genomics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366904/ https://www.ncbi.nlm.nih.gov/pubmed/25742468 http://dx.doi.org/10.1038/bjc.2015.79 |
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