Comparative analysis of the mutational landscape and evolutionary patterns of pancreatic ductal adenocarcinoma metastases in the liver or peritoneum
Guoliang Yao,
Yanfeng Zhu,
Chunhui Liu,
Yanwen Man,
Kefeng Liu,
Qin Zhang,
Yuan Tan,
Qianqian Duan,
Dongsheng Chen,
Zunguo Du,
Yonggang Fan
Affiliations
Guoliang Yao
Department of General Surgery, The First Affiliated Hospital of Henan University of Science and Technology, 636 Guanlin Road, Luoyang, China
Yanfeng Zhu
Department of Nursing, Huashan Hospital, Fudan University, No.12 Middle Urumqi Road, Shangha, China
Chunhui Liu
Department of General Surgery, The First Affiliated Hospital of Henan University of Science and Technology, 636 Guanlin Road, Luoyang, China
Yanwen Man
Department of General Surgery, The First Affiliated Hospital of Henan University of Science and Technology, 636 Guanlin Road, Luoyang, China
Kefeng Liu
Department of General Surgery, The First Affiliated Hospital of Henan University of Science and Technology, 636 Guanlin Road, Luoyang, China
Qin Zhang
Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd., The State Key Laboratory of Neurology and Oncology Drug Development, China
Yuan Tan
Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd., The State Key Laboratory of Neurology and Oncology Drug Development, China
Qianqian Duan
Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd., The State Key Laboratory of Neurology and Oncology Drug Development, China
Dongsheng Chen
Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd., The State Key Laboratory of Neurology and Oncology Drug Development, China
Zunguo Du
Department of Pathology, Huashan Hospital, Fudan University, No.12 Middle Urumqi Road, Shanghai, China; Corresponding author. Department of Pathology, Huashan Hospital, Fudan University, No.12 Middle Urumqi Road, Shanghai, China.
Yonggang Fan
Department of General Surgery, The First Affiliated Hospital of Henan University of Science and Technology, 636 Guanlin Road, Luoyang, China; Corresponding author.
Background: Pancreatic ductal adenocarcinoma (PDAC) often presents with liver or peritoneal metastases at diagnosis. Despite similar treatment approaches, patient outcomes vary between these metastatic sites. To improve targeted therapies for metastatic PDAC, a comprehensive analysis of the genetic profiles and evolutionary patterns at these distinct metastatic locations is essential. Methods: We performed whole exome sequencing on 44 tissue samples from 27 PDAC patients, including primary tumours and matched liver or peritoneal metastases. We analysed somatic mutation profiles, signatures, and affected pathways for each group, and examined clonal evolution using subclonal architectures and phylogenetic trees. Results: KRAS mutations remained the predominant driver alteration, with a prevalence of 89 % across all tumours. Notably, we observed site-specific differences in mutation frequencies, with KRAS alterations detected in 77.8 % (7/9) of peritoneal metastases and 87.5 % (7/8) of liver metastases. TP53 mutations exhibited a similar pattern, occurring in 55.6 % (5/9) of peritoneal and 37.5 % (3/8) of liver metastases. Intriguingly, we identified site-specific alterations in DNA repair pathway genes, including ATM and BRCA1, with distinct mutational profiles in liver versus peritoneal metastases. Furthermore, liver metastases demonstrated a significantly higher tumor mutational burden (TMB) compared to peritoneal metastases (median [IQR]: 2.14 [1.77–2.71] vs. 1.29 [1.21–1.69] mutations/Mb; P = 0.048). Conclusions: In conclusion, metastasis of pancreatic cancer may be influenced by variables other than KRAS mutations, such as TP53. PDAC peritoneal and liver metastases may differ in potential therapeutic biomarkers. Further inquiry is needed on the biological mechanisms underlying metastasis and the treatment of diverse metastases.
