An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer
Zhijun Zhou,
Junxia Zhang,
Chao Xu,
Jingxuan Yang,
Yuqing Zhang,
Mingyang Liu,
Xiuhui Shi,
Xiaoping Li,
Hanxiang Zhan,
Wei Chen,
Lacey R. McNally,
Kar-Ming Fung,
Wenyi Luo,
Courtney W. Houchen,
Yulong He,
Changhua Zhang,
Min Li
Affiliations
Zhijun Zhou
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Junxia Zhang
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Chao Xu
Department of Biostatistics and Epidemiology, Hudson College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Jingxuan Yang
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Yuqing Zhang
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Mingyang Liu
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Xiuhui Shi
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Xiaoping Li
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Hanxiang Zhan
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Wei Chen
Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, Guangdong 518107, China
Lacey R. McNally
Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Kar-Ming Fung
Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Wenyi Luo
Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Courtney W. Houchen
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
Yulong He
Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, Guangdong 518107, China
Changhua Zhang
Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, Guangdong 518107, China; Corresponding authors.
Min Li
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Corresponding authors.
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.
