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An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer

BACKGROUND: N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: An integrated model named “m6Ascore” is constructed based on RNA-seq...

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Autores principales: Zhou, Zhijun, Zhang, Junxia, Xu, Chao, Yang, Jingxuan, Zhang, Yuqing, Liu, Mingyang, Shi, Xiuhui, Li, Xiaoping, Zhan, Hanxiang, Chen, Wei, McNally, Lacey R., Fung, Kar-Ming, Luo, Wenyi, Houchen, Courtney W., He, Yulong, Zhang, Changhua, Li, Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966986/
https://www.ncbi.nlm.nih.gov/pubmed/33714027
http://dx.doi.org/10.1016/j.ebiom.2021.103271
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author Zhou, Zhijun
Zhang, Junxia
Xu, Chao
Yang, Jingxuan
Zhang, Yuqing
Liu, Mingyang
Shi, Xiuhui
Li, Xiaoping
Zhan, Hanxiang
Chen, Wei
McNally, Lacey R.
Fung, Kar-Ming
Luo, Wenyi
Houchen, Courtney W.
He, Yulong
Zhang, Changhua
Li, Min
author_facet Zhou, Zhijun
Zhang, Junxia
Xu, Chao
Yang, Jingxuan
Zhang, Yuqing
Liu, Mingyang
Shi, Xiuhui
Li, Xiaoping
Zhan, Hanxiang
Chen, Wei
McNally, Lacey R.
Fung, Kar-Ming
Luo, Wenyi
Houchen, Courtney W.
He, Yulong
Zhang, Changhua
Li, Min
author_sort Zhou, Zhijun
collection PubMed
description BACKGROUND: N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: An integrated model named “m6Ascore” is constructed based on RNA-seq data of m6A regulators in PDAC. Association of m6Ascore and overall survival is validated across several different datasets. Overlaps of m6Ascore and established molecular classifications of PDAC is examined. Immune infiltration, enriched pathways, somatic copy number alterations (SCNAs), mutation profiles and response to immune checkpoint inhibitors are compared between m6Ascore-high and m6Ascore-low tumors. FINDINGS: m6Ascore is associated with dismal overall survival and increased tumor recurrence in PDAC as well as several other solid tumors including colorectal cancer and breast cancer. Basal-like (Squamous) PDAC has higher m6Ascore than that in the classical PDAC. Mechanism study showed m6Ascore-high tumors are characterized with reduced immune infiltration and T cells exhaustion. Meanwhile, m6Ascore is associated with genes regulating cachexia and chemoresistance in PDAC. Furthermore, distinct SCNAs patterns and mutation profiles of KRAS and TP53 are present in m6Ascore-high tumors, indicating immune evasion. m6Ascore-low tumors have higher response rates to immune checkpoint inhibitors (ICIs). INTERPRETATION: These findings indicate m6Ascore can predict aggressiveness and immune evasion in pancreatic cancer. This model has implications for pancreatic cancer prognosis and treatment response to ICIs. FUNDING: This work was supported in part by National Institutes of Health (NIH) grants to M. Li (R01 CA186338, R01 CA203108, R01 CA247234 and the William and Ella Owens Medical Research Foundation) and NIH/National Cancer Institute Q39 award P30CA225520 to Stephenson Cancer Center.
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spelling pubmed-79669862021-03-19 An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer Zhou, Zhijun Zhang, Junxia Xu, Chao Yang, Jingxuan Zhang, Yuqing Liu, Mingyang Shi, Xiuhui Li, Xiaoping Zhan, Hanxiang Chen, Wei McNally, Lacey R. Fung, Kar-Ming Luo, Wenyi Houchen, Courtney W. He, Yulong Zhang, Changhua Li, Min EBioMedicine Research paper BACKGROUND: N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: An integrated model named “m6Ascore” is constructed based on RNA-seq data of m6A regulators in PDAC. Association of m6Ascore and overall survival is validated across several different datasets. Overlaps of m6Ascore and established molecular classifications of PDAC is examined. Immune infiltration, enriched pathways, somatic copy number alterations (SCNAs), mutation profiles and response to immune checkpoint inhibitors are compared between m6Ascore-high and m6Ascore-low tumors. FINDINGS: m6Ascore is associated with dismal overall survival and increased tumor recurrence in PDAC as well as several other solid tumors including colorectal cancer and breast cancer. Basal-like (Squamous) PDAC has higher m6Ascore than that in the classical PDAC. Mechanism study showed m6Ascore-high tumors are characterized with reduced immune infiltration and T cells exhaustion. Meanwhile, m6Ascore is associated with genes regulating cachexia and chemoresistance in PDAC. Furthermore, distinct SCNAs patterns and mutation profiles of KRAS and TP53 are present in m6Ascore-high tumors, indicating immune evasion. m6Ascore-low tumors have higher response rates to immune checkpoint inhibitors (ICIs). INTERPRETATION: These findings indicate m6Ascore can predict aggressiveness and immune evasion in pancreatic cancer. This model has implications for pancreatic cancer prognosis and treatment response to ICIs. FUNDING: This work was supported in part by National Institutes of Health (NIH) grants to M. Li (R01 CA186338, R01 CA203108, R01 CA247234 and the William and Ella Owens Medical Research Foundation) and NIH/National Cancer Institute Q39 award P30CA225520 to Stephenson Cancer Center. Elsevier 2021-03-10 /pmc/articles/PMC7966986/ /pubmed/33714027 http://dx.doi.org/10.1016/j.ebiom.2021.103271 Text en © 2021 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 Research paper
Zhou, Zhijun
Zhang, Junxia
Xu, Chao
Yang, Jingxuan
Zhang, Yuqing
Liu, Mingyang
Shi, Xiuhui
Li, Xiaoping
Zhan, Hanxiang
Chen, Wei
McNally, Lacey R.
Fung, Kar-Ming
Luo, Wenyi
Houchen, Courtney W.
He, Yulong
Zhang, Changhua
Li, Min
An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer
title An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer
title_full An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer
title_fullStr An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer
title_full_unstemmed An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer
title_short An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer
title_sort integrated model of n6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966986/
https://www.ncbi.nlm.nih.gov/pubmed/33714027
http://dx.doi.org/10.1016/j.ebiom.2021.103271
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