| Popis: |
PurposeUsing a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; MethodsWe analyzed matched whole-transcriptome and DNA sequencing data from 2430 patient samples (YOPC, n=292; AOPC, n=2138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data was obtained from insurance claims (n=4928); Kaplan-Meier estimates were calculated for age-and molecularly-defined cohorts. Significance was determined as FDR-correctedP-values (Q)ResultsYOPC patients had higher proportions of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H),BRCA2-mutant, andPALB2-mutant tumors compared with AOPC patients, but fewerSMAD4-, RNF43-, CDKN2A-, andSF3B1-mutant tumors. Notably, YOPC patients demonstrated significantly lower incidence ofKRASmutations compared with AOPC patients (81.3% vs. 90.9%;Q=0.004). In theKRAS-wildtype subset (n=227), YOPC tumors demonstrated fewerTP53mutations and were more likely driven byNRG1andMETfusions, whileBRAFfusions were exclusively observed in AOPC patients. Immune deconvolution revealed significant enrichment of natural killer (NK) cells, CD8+T cells, monocytes, and M2 macrophages in YOPC patients relative to AOPC patients, which corresponded with lower rates ofHLA-DPA1homozygosity. There was an association with improved OS in YOPC patients compared with AOPC patients withKRAS-wildtype tumors (median 16.2 [YOPC-KRASWT] vs. 10.6 [AOPC-KRASWT] months;P=0.008) but notKRAS-mutant tumors (P=0.084).ConclusionIn this large, real-world multi-omic characterization of age-stratified molecular differences in PDAC, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications. |
