Multiomic Characterization Reveals a Distinct Molecular Landscape in Young-Onset Pancreatic Cancer.

Purpose: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between patients with young-onset pancreatic cancer (YOPC; younger than 50 years) and patients with average-onset pancreatic cancer (AOPC; 70 years and older).

Methods: We analyzed matched whole-transcriptome and DNA sequencing data from 2,430 patient samples (YOPC, n = 292; AOPC, n = 2,138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data were obtained from insurance claims (n = 4,928); Kaplan-Meier estimates were calculated for age- and molecularly defined cohorts. Significance was determined as FDR-corrected values () < .05.

Results: Patients with YOPC had higher proportions of mismatch repair-deficient/microsatellite instability-high, -mutant, and -mutant tumors compared with patients with AOPC, but fewer , , , and mutant tumors. Notably, patients with YOPC demonstrated significantly lower incidence of mutations compared with patients with AOPC (81.3% 90.9%; = .004). In the wild-type subset (n = 227), YOPC tumors demonstrated fewer mutations and were more likely driven by and fusions, whereas fusions were exclusively observed in patients with AOPC. Immune deconvolution revealed significant enrichment of natural killer cells, CD8 T cells, monocytes, and M2 macrophages in patients with YOPC relative to patients with AOPC, which corresponded with lower rates of homozygosity. There was an association with improved OS in patients with YOPC compared with patients with AOPC with wild-type tumors (median, 16.2 [YOPC-] 10.6 [AOPC-] months; = .008) but not -mutant tumors ( = .084).

Conclusion: In this large, real-world multiomic characterization of age-stratified molecular differences in pancreatic ductal adenocarcinoma, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.