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

Abstract

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). 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 <i>P</i> values (<i>Q</i>) < .05. Patients with YOPC had higher proportions of mismatch repair-deficient/microsatellite instability-high, <i>BRCA2</i>-mutant, and <i>PALB2</i>-mutant tumors compared with patients with AOPC, but fewer <i>SMAD4-</i>, <i>RNF43-</i>, <i>CDKN2A-</i>, and <i>SF3B1-</i>mutant tumors. Notably, patients with YOPC demonstrated significantly lower incidence of <i>KRAS</i> mutations compared with patients with AOPC (81.3% <i>v</i> 90.9%; <i>Q</i> = .004). In the <i>KRAS</i> wild-type subset (n = 227), YOPC tumors demonstrated fewer <i>TP53</i> mutations and were more likely driven by <i>NRG1</i> and <i>MET</i> fusions, whereas <i>BRAF</i> 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 <i>HLA-DPA1</i> homozygosity. There was an association with improved OS in patients with YOPC compared with patients with AOPC with <i>KRAS</i> wild-type tumors (median, 16.2 [YOPC-<i>KRAS</i>^WT] <i>v</i> 10.6 [AOPC-<i>KRAS</i>^WT] months; <i>P</i> = .008) but not <i>KRAS</i>-mutant tumors (<i>P</i> = .084). 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.