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Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is a well-known lethal and heterogeneous disease. Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) is an important mutagenic driver that has seldom been investigated in PDAC. Therefore, this study investigated the significance of APOBEC...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232547/ https://www.ncbi.nlm.nih.gov/pubmed/35750693 http://dx.doi.org/10.1038/s41389-022-00411-9 |
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author | Qian, Yunzhen Gong, Yitao Zou, Xuan Liu, Yu Chen, Yusheng Wang, Ruijie Dai, Zhengjie Tasiheng, Yesiboli Lin, Xuan Wang, Xu Luo, Guopei Yu, Xianjun Cheng, He Liu, Chen |
author_facet | Qian, Yunzhen Gong, Yitao Zou, Xuan Liu, Yu Chen, Yusheng Wang, Ruijie Dai, Zhengjie Tasiheng, Yesiboli Lin, Xuan Wang, Xu Luo, Guopei Yu, Xianjun Cheng, He Liu, Chen |
author_sort | Qian, Yunzhen |
collection | PubMed |
description | Pancreatic ductal adenocarcinoma (PDAC) is a well-known lethal and heterogeneous disease. Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) is an important mutagenic driver that has seldom been investigated in PDAC. Therefore, this study investigated the significance of APOBEC3C in PDAC. First, cytosine deamination-associated mutation signatures were identified in the PDAC cohorts from TCGA and Fudan University Shanghai Cancer Center (FUSCC) datasets, and C > X-enriched kataegis regions were identified in the FUSCC cohort (12 to 27 counts per sample). Patients were stratified according to APOBEC3C expression, and high APOBEC3C expression was found to correlate with a higher motif enrichment score of 5’-CC-3’ and an elevated kataegis count within PCSK5 and NES genes. Second, we compared APOBEC expression in PDAC and normal pancreatic tissues and found that APOBEC3C was substantially upregulated in PDAC. APOBEC3C-overexpressing cell lines were generated to substantiate the effects of APOBEC3C on PDAC genome, including alterations in single-nucleotide variant (SNV) classes (higher proportion of C > T conversions) and the formation of kataegis regions (newly occurring kataegis regions detected in ACHE and MUC6 genes). Three different PDAC cohorts (FUSCC, TCGA, and QCMG) were analysed to evaluate the prognostic value of APOBEC3C, and APOBEC3C overexpression predicted shorter survival. Finally, the APOBEC3C overexpression correalted with the PDAC tumour microenvironment (TME) remodelling, APOBEC3C expression was associated with the invasion of CD4 + T lymphocytes and CD8 + T lymphocytes (cytotoxic T lymphocytes, CTLs), indicating enhanced immune activity and validating the practicality of APOBEC3C for guiding immunotherapy. |
format | Online Article Text |
id | pubmed-9232547 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92325472022-06-26 Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma Qian, Yunzhen Gong, Yitao Zou, Xuan Liu, Yu Chen, Yusheng Wang, Ruijie Dai, Zhengjie Tasiheng, Yesiboli Lin, Xuan Wang, Xu Luo, Guopei Yu, Xianjun Cheng, He Liu, Chen Oncogenesis Article Pancreatic ductal adenocarcinoma (PDAC) is a well-known lethal and heterogeneous disease. Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) is an important mutagenic driver that has seldom been investigated in PDAC. Therefore, this study investigated the significance of APOBEC3C in PDAC. First, cytosine deamination-associated mutation signatures were identified in the PDAC cohorts from TCGA and Fudan University Shanghai Cancer Center (FUSCC) datasets, and C > X-enriched kataegis regions were identified in the FUSCC cohort (12 to 27 counts per sample). Patients were stratified according to APOBEC3C expression, and high APOBEC3C expression was found to correlate with a higher motif enrichment score of 5’-CC-3’ and an elevated kataegis count within PCSK5 and NES genes. Second, we compared APOBEC expression in PDAC and normal pancreatic tissues and found that APOBEC3C was substantially upregulated in PDAC. APOBEC3C-overexpressing cell lines were generated to substantiate the effects of APOBEC3C on PDAC genome, including alterations in single-nucleotide variant (SNV) classes (higher proportion of C > T conversions) and the formation of kataegis regions (newly occurring kataegis regions detected in ACHE and MUC6 genes). Three different PDAC cohorts (FUSCC, TCGA, and QCMG) were analysed to evaluate the prognostic value of APOBEC3C, and APOBEC3C overexpression predicted shorter survival. Finally, the APOBEC3C overexpression correalted with the PDAC tumour microenvironment (TME) remodelling, APOBEC3C expression was associated with the invasion of CD4 + T lymphocytes and CD8 + T lymphocytes (cytotoxic T lymphocytes, CTLs), indicating enhanced immune activity and validating the practicality of APOBEC3C for guiding immunotherapy. Nature Publishing Group UK 2022-06-24 /pmc/articles/PMC9232547/ /pubmed/35750693 http://dx.doi.org/10.1038/s41389-022-00411-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Qian, Yunzhen Gong, Yitao Zou, Xuan Liu, Yu Chen, Yusheng Wang, Ruijie Dai, Zhengjie Tasiheng, Yesiboli Lin, Xuan Wang, Xu Luo, Guopei Yu, Xianjun Cheng, He Liu, Chen Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma |
title | Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma |
title_full | Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma |
title_fullStr | Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma |
title_full_unstemmed | Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma |
title_short | Aberrant APOBEC3C expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma |
title_sort | aberrant apobec3c expression induces characteristic genomic instability in pancreatic ductal adenocarcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232547/ https://www.ncbi.nlm.nih.gov/pubmed/35750693 http://dx.doi.org/10.1038/s41389-022-00411-9 |
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