Characterization of the genomic landscape in large-scale Chinese patients with pancreatic cancer
Xiaofei Zhang,
Tiebo Mao,
Bei Zhang,
Haiyan Xu,
Jiujie Cui,
Feng Jiao,
Dongqin Chen,
Yu Wang,
Jiong Hu,
Qing Xia,
Weiyu Ge,
Shumin Li,
Ming Yue,
Jingyu Ma,
Jiayu Yao,
Yongchao Wang,
Yanling Wang,
Daiyuan Shentu,
Xiao Zhang,
Shiqing Chen,
Yuezong Bai,
Yuexiang Wang,
Xuebin Zhang,
Qiang Liu,
Yongwei Sun,
Deliang Fu,
Yingbin Liu,
Lei Xiong,
Liwei Wang
Affiliations
Xiaofei Zhang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Tiebo Mao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Bei Zhang
The Medical Department, 3D Medicines Inc., Shanghai, China
Haiyan Xu
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Jiujie Cui
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Feng Jiao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Dongqin Chen
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yu Wang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Jiong Hu
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Qing Xia
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Weiyu Ge
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shumin Li
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Ming Yue
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Jingyu Ma
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Jiayu Yao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yongchao Wang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yanling Wang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Daiyuan Shentu
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Xiao Zhang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shiqing Chen
The Medical Department, 3D Medicines Inc., Shanghai, China
Yuezong Bai
The Medical Department, 3D Medicines Inc., Shanghai, China
Yuexiang Wang
Head of Laboratory of Cancer Progression and Translational Medicine Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
Xuebin Zhang
Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Qiang Liu
Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Yongwei Sun
Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Deliang Fu
Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
Yingbin Liu
Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Lei Xiong
The Medical Department, 3D Medicines Inc., Shanghai, China; Lei Xiong, The Medical Department, 3D Medicines Inc., Shanghai 201321, China. Phone: +8618616780995.
Liwei Wang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Corresponding Authors: Liwei Wang, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160, Pujian Road, Pudong District, Shanghai 200127, China. Phone: +8613761254228.
Summary: Background: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with an extremely poor prognosis. Effective targets for anticancer therapy confirmed in PDAC are limited. However, the characteristics of genomics have not been fully elucidated in large-scale patients with PDAC from China. Methods: We collected both blood and tissue samples from 1080 Chinese patients with pancreatic cancer and retrospectively investigated the genomic landscape using next-generation sequencing (NGS). Findings: We found recurrent somatic mutations in KRAS (83.2%), TP53 (70.6%), CDKN2A (28.8%), SMAD4 (23.0%), ARID1A (12.8%) and CDKN2B (8.9%) in Chinese PDAC patients. Compared with primary pancreatic cancers, more genomic alterations accumulated especially cell cycle regulatory gene variants (45.4% vs 31.6%, P < 0.001) were observed in metastatic tumors. The most common mutation site of KRAS is p.G12D (43.6%) in pancreatic cancer. Patients with KRAS mutations were significantly associated with older age and mutations in the other three driver genes, while KRAS wild-type patients contained more fusion mutations and alternative mechanisms of RTK/Ras/MAPK pathway including a number of clinically targetable mutations. KRAS mutations in Chinese cohort were significantly lower than those in Western cohorts (all P < 0.05). A total of 252 (23.3%) patients with the core DNA damage response (DDR) gene mutations were detected. ATM (n =59, 5.5%) was the most frequent mutant DDR gene in patients with pancreatic cancer from China. Patients with germline DDR gene mutations were younger (P = 0.018), while patients with somatic DDR gene mutations were more likely to accumulate in metastatic lesions (P < 0.001) and had higher TMB levels (P < 0.001). In addition, patients with mutant DDR genes and patients carrying TP53 mutation were observed mutually exclusive (P < 0.001). Interpretation: We demonstrated the real-world genomic characteristics of large-scale patients with pancreatic cancer from China which may have promising implications for further clinical significance and drug development. Funding: The funders are listed in the Acknowledgement.
