The enhanced cell cycle related to the response to adjuvant therapy in pancreatic ductal adenocarcinoma

Yize Mao; Weisheng Cheng; Qiuxia Yang; Liqin Li; Wanming Hu; Zeyu Shuang; Dejun Fan; Xinlei Jiang; Feng Gao; Shengping Li; Wei Wang

doi:10.1016/j.ygeno.2021.11.036

The enhanced cell cycle related to the response to adjuvant therapy in pancreatic ductal adenocarcinoma

Genomics. 2022 Jan;114(1):95-106. doi: 10.1016/j.ygeno.2021.11.036. Epub 2021 Dec 1.

Authors

Yize Mao¹, Weisheng Cheng², Qiuxia Yang³, Liqin Li⁴, Wanming Hu⁵, Zeyu Shuang⁶, Dejun Fan⁷, Xinlei Jiang⁸, Feng Gao⁹, Shengping Li¹⁰, Wei Wang¹¹

Affiliations

¹ Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
² Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Prenatal Diagnosis Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China.
³ Department of Medical Imaging Center, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
⁴ Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou Hospital affiliated with Zhejiang University, Huzhou, Zhejiang, China.
⁵ Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
⁶ Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
⁷ Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510655, China.
⁸ Tianjin Key Laboratory of Aquatic Science and Technology, School of Environmental and Municipal Engineering, Tianjin Chengjian University, Tianjin, China.
⁹ Department of Colorectal Surgery, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Supported by National Key Clinical Discipline, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510655, China. Electronic address: gaof57@mail.sysu.edu.cn.
¹⁰ Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address: lishp@sysucc.org.cn.
¹¹ Biomedical Big Data Center, Department of Gynecology, Huzhou Maternity & Child Health Care Hospital, Huzhou 313000, Zhejiang Province, China. Electronic address: wwscu1218@163.com.

PMID: 34863899
DOI: 10.1016/j.ygeno.2021.11.036

Abstract

A major clinical challenge for treating patients with pancreatic ductal adenocarcinoma (PDAC) is identifying those that may benefit from adjuvant chemotherapy versus those that will not. Thus, there is a need for a robust and convenient biomarker for predicting chemotherapy response in PDAC patients. In this study, network inference was conducted by integrating the differentially expressed cell cycle signatures and target genes between the basal-like subtype and classical subtype of PDAC. As a result from this statistical analysis, two dominant cell cycle genes, RASAL2 and ASPM, were identified. Based on the expression levels of these two genes, we constructed a "Enhanced Cell Cycle" scoring system (ECC score). Patients were given an ECC score, and respectively divided into ECC-high and ECC-low groups. Survival, pathway enrichment, immune environment characteristics, and chemotherapy response analysis' were performed between the two groups in a total of 891 patients across 5 cohorts. ECC-high patients exhibited shortened recurrence-free survival (RFS) and overall survival (OS) rates. In addition, it was found that adjuvant chemotherapy could significantly improve the outcome of the ECC-high patients while ECC-low patients did not benefit from adjuvant chemotherapy. It was also found that there was less CD8+ T cell, natural killer (NK) cell, M1 macrophage, and plasma cell infiltration in ECC-high patients when compared to ECC-low patients. Also, the expression of CD73, an immune suppressor gene, and it's related hypoxia pathway were elevated in the ECC-high group when compared to the ECC-low group. In conclusion, this study showed that patients characterized as ECC-high not only had reduced RFS and OS rates, but were also more sensitive to adjuvant chemotherapy and could potentially be less sensitive to immune checkpoint inhibitors. Being able to characterize patients by these parameters would allow doctors to make more informed decisions on patient treatment regimens.

Keywords: Adjuvant chemotherapy; Cell cycle; Immunotherapy; Pancreatic ductal adenocarcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Cell Cycle* / drug effects
Cell Cycle* / genetics
Chemotherapy, Adjuvant
Combined Modality Therapy
GTPase-Activating Proteins
Humans
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics

Substances

GTPase-Activating Proteins
RASAL2 protein, human