Comparative analysis of the mutational landscape and evolutionary patterns of pancreatic ductal adenocarcinoma metastases in the liver or peritoneum.

[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] mutations remained the predominant driver alteration, with a prevalence of 89 % across all tumours. Notably, we observed site-specific differences in mutation frequencies, with alterations detected in 77.8 % (7/9) of peritoneal metastases and 87.5 % (7/8) of liver metastases. 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 and , 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 mutations, such as . 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.