Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features

Simple Summary Pancreatic ducal adenocarcinoma (PDAC) is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years old (y.o.). Multiple molecular defects such as DNA damages and oxidative stress present in PDAC are associated with ageing. With a multiomics approach, we assessed the molecular features of early-onset tumors (<= 55 y.o.) and compared them to classical late-onset tumors (>= 70 y.o.). Our results demonstrated that tumors from both groups showed a similar molecular profile. Given that young patients are more often included in clinical trials, this absence of difference is an important finding that supports younger patients as a good molecular surrogate model for the general older population of patients with PDAC. Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is known to impact DNA methylation and proteome integrity through carbonylation-related oxidative damages. We therefore aimed to assess the global molecular features of EOT. We compared 176 EOT (<= 55 y.o.) and 316 LOT (>= 70 y.o.) from three distinct surgical cohorts at the clinical/genomic/epigenomic/transcriptomic level. Furthermore, we assessed oxidative stress responses and oxidative proteome damages using 2D gel electrophoresis followed by mass spectrometry protein identification. There was no consistent clinical difference between EOT and LOT across the three cohorts. The mutational landscape of key driver genes and the global methylation profile were similar in the two groups. LOT did display age-related features such as enriched DNA repair gene signatures and upregulation of oxidative stress defenses together with increased proteome carbonylation. However, these age-related differences were more preeminent in non-tumor tissues while tumor proteome and proteome damages were fairly comparable. In conclusion, this multi-omics comparison showed that EOT harbor a comparable molecular profile to that of LOT.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed in the 7th decade, but around 10% of patients are diagnosed before the age of 55. Molecular features of early-onset tumors (<= 55 y.o.) were found to be similar to late-onset tumors (>= 70 y.o.), indicating that younger patients can serve as a good molecular surrogate model for the general older population with PDAC. The study also highlighted the impact of ageing on DNA methylation and proteome integrity, as well as the association of oxidative stress responses with PDAC.